U.S. patent number 10,172,810 [Application Number 15/148,106] was granted by the patent office on 2019-01-08 for transmucosal ketamine delivery composition.
This patent grant is currently assigned to Pharmaceutical Productions, Inc.. The grantee listed for this patent is PHARMACEUTICAL PRODUCTIONS INC.. Invention is credited to John A. McCarty.
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United States Patent |
10,172,810 |
McCarty |
January 8, 2019 |
Transmucosal ketamine delivery composition
Abstract
Disclosed are preparations and formulations of high
thermodynamic activity lipophilic associations (LA), in which there
is pairing between an ionizable pharmaceutical agent and a
lipophilic species having ionic characteristics opposite to that of
the pharmaceutical agent. Such lipophilic associations manifest
high thermodynamic activity, as evidenced by their being
predominantly in a liquid phase at room temperature or solvated in
a lower-than-water dielectric solvent. Further the pharmaceutical
agent being solubilized means that dissolution is not rate limiting
to transmucosal absorption. This LA or LA-solvate is formulated
into a low dielectric dosage form, from when, upon the dosage
form's hydration, the pharmaceutical agent is driven through the
mucosal tissue and into systemic circulation. The invention
therefore provides an enhanced transmucosal drug delivery system
for ionizable pharmaceutical agents at or near physiological
pH.
Inventors: |
McCarty; John A. (Miami
Springs, FL) |
Applicant: |
Name |
City |
State |
Country |
Type |
PHARMACEUTICAL PRODUCTIONS INC. |
Miami Springs |
FL |
US |
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Assignee: |
Pharmaceutical Productions,
Inc. (Miami Springs, FL)
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Family
ID: |
56852002 |
Appl.
No.: |
15/148,106 |
Filed: |
May 6, 2016 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20160256415 A1 |
Sep 8, 2016 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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14211317 |
Mar 14, 2014 |
9358296 |
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10545774 |
Mar 31, 2015 |
8992974 |
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PCT/US2004/005490 |
Feb 24, 2004 |
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60449647 |
Feb 24, 2003 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
9/2095 (20130101); A61K 9/006 (20130101); A61K
47/26 (20130101); A61K 9/2031 (20130101); A61K
9/2018 (20130101); A61K 9/2059 (20130101); A61K
47/36 (20130101); A61K 9/2013 (20130101); A61K
31/465 (20130101); A61K 47/14 (20130101); A61K
9/2009 (20130101); A61K 9/08 (20130101); A61K
47/12 (20130101); A61K 9/20 (20130101); A61K
31/135 (20130101); A61K 47/38 (20130101); A61K
47/543 (20170801) |
Current International
Class: |
A61K
31/135 (20060101); A61K 9/08 (20060101); A61K
9/20 (20060101); A61K 47/38 (20060101); A61K
47/26 (20060101); A61K 47/14 (20170101); A61K
9/00 (20060101); A61K 31/465 (20060101); A61K
47/36 (20060101); A61K 47/12 (20060101); A61K
47/54 (20170101) |
Field of
Search: |
;514/647
;424/464,490 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0387647 |
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Sep 1990 |
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EP |
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2001/508027 |
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Jun 2001 |
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JP |
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2001/517624 |
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Oct 2001 |
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JP |
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2001/521882 |
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Nov 2001 |
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JP |
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62/11607 |
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Oct 2017 |
|
JP |
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WO-98/02187 |
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Jan 1998 |
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WO |
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WO-99/15171 |
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Apr 1999 |
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WO |
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WO-99/22703 |
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May 1999 |
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WO |
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WO-01/22937 |
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Apr 2001 |
|
WO |
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WO-2004075877 |
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Sep 2004 |
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WO |
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WO-2005/087199 |
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Sep 2005 |
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WO |
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Other References
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.
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updated Dec. 14, 2009. cited by applicant .
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of Product characteristics last updated Apr. 7, 2010. cited by
applicant .
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on the Percuataneous Absorption of Propanolol," J Pharmaceut Sci,
78(12):2-8 (1990). cited by applicant .
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Nicotine Aerosol Delivery Device (INADD)," Psychopharmacology,
108:519-526 (1992). cited by applicant .
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applicant.
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Primary Examiner: Tran; My-Chau T.
Attorney, Agent or Firm: Foley Hoag LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of U.S. Ser. No.
14/211,317, filed on Mar. 14, 2014, which is a continuation-in-part
of U.S. Ser. No. 10/545,774, filed on Aug. 8, 2006, now U.S. Pat.
No. 8,992,974, which issued on Mar. 31, 2015, which is a National
Stage application under 35 U.S.C. .sctn. 371 and claims benefit
under 35 U.S.C. .sctn. 119(a) of International Application No.
PCT/US2004/005490, having an International Filing Date of Feb. 24,
2004, which claims benefit of U.S. Provisional Application Ser. No.
60/449,647 filed on Feb. 24, 2003, the contents of each of which
are incorporated herein by reference in their entireties. This
application is also related to U.S. Ser. No. 14/634,693, filed on
Feb. 27, 2015.
Claims
The invention claimed is:
1. A pharmaceutical composition, comprising: a solid adsorbent;
and, adsorbed thereto, a liquid solution of Ketamine and a fatty
acid, wherein the solid adsorbent is a silica or silicified
microcrystalline cellulose; and the pharmaceutical composition is a
solid dosage form.
2. The pharmaceutical composition of claim 1, wherein the fatty
acid is caproic acid, oleic acid, caprylic acid, lauric acid,
myristic acid, palmitic acid, stearic acid, arachidic acid, behenic
acid, lignoceric acid, myristoleic acid, palmitoleic acid, gadoleic
acid, erucic acid, ricinoleic acid, linoleic acid, linoleic acid,
licanic acid, arachidonic acid, clupanodonic acid, or mixtures
thereof.
3. The pharmaceutical composition of claim 2, wherein the fatty
acid comprises oleic acid.
4. The pharmaceutical composition of claim 1, wherein the
pharmaceutical composition further comprises a co-solvent.
5. The pharmaceutical composition of claim 4, wherein the
co-solvent comprises polyethylene glycol (PEG), ethanol, ethyl
acetate, isopropyl alcohol, triacetin, triethyl citrate, tributyl
citrate, substituted polyethylene glycols, bisabolol, glycerin,
mineral oil, ethyl oleate, squalane, animal oils, vegetable oils,
propylene glycol, hydrogenated vegetable oils, isopropyl myristate,
isopropyl palmitate, glycofurol, terpenes, essential oils,
alcohols, polyols, silicone fluids, or mixtures thereof.
6. The pharmaceutical composition of claim 5, wherein the
co-solvent comprises ethanol.
7. The pharmaceutical composition of claim 1, wherein the
pharmaceutical composition further comprises a solid, water-soluble
excipient; a disintegrant; a lubricant; or mixtures thereof.
8. The pharmaceutical composition of claim 7, wherein the
pharmaceutical composition further comprises a co-solvent.
9. The pharmaceutical composition of claim 7, wherein the
pharmaceutical composition further comprises a solid, water-soluble
excipient; and the solid, water-soluble excipient is selected from
the group consisting of a sugar, a polyol, a saccharide, a
polysaccharide, a dextrate, a dextrin, dextrose, fructose,
lactitol, lactose, erythritol, maltose, maltitol, a maltodextrin, a
polydextrose, trehalose, mannitol, a polyethylene glycol, sorbitol,
sucrose, xylitol and mixtures thereof.
10. The pharmaceutical composition of claim 9, wherein the solid,
water-soluble excipient comprises mannitol.
11. The pharmaceutical composition of claim 9, wherein the
pharmaceutical composition further comprises a disintegrant; and
the disintegrant is selected from the group consisting of sodium
starch glycolate, crospovidone, croscarmellose sodium,
low-substituted hydroxypropyl cellulose, starch, microcrystalline
cellulose and mixtures thereof.
12. The pharmaceutical composition of claim 11, wherein the
disintegrant comprises low-substituted hydroxypropyl cellulose.
13. The pharmaceutical composition of claim 7, wherein the
pharmaceutical composition further comprises a lubricant; and the
lubricant is selected from the group consisting of sodium stearyl
fumarate, magnesium stearate, stearic acid, sodium lauryl sulfate,
talc, polyethylene glycol, calcium stearate and mixtures
thereof.
14. The pharmaceutical composition of claim 13, wherein the
lubricant comprises sodium stearyl fumarate.
15. The pharmaceutical composition of claim 1, comprising: about
0.1 mg to about 20 mg ketamine; about 0.4 mg to about 80 mg fatty
acid; and up to about 200 mg solid adsorbent.
16. The pharmaceutical composition of claim 15, further comprising
a co-solvent in an amount up to about 50 mg.
17. The pharmaceutical composition of claim 15, further comprising:
about 25 mg to about 500 mg solid, water-soluble excipient; about
0.5 mg to about 150 mg disintegrant; and/or about 0.1 mg to about
20 mg lubricant.
18. The pharmaceutical composition of claim 1, wherein the solid
dosage form is a tablet.
19. A process for the preparation of the pharmaceutical composition
of claim 1, comprising: solvating ketamine in the fatty acid to
form a solvated drug solution; and adsorbing the solvated drug
solution to the solid adsorbent, wherein the solvated drug solution
is in liquid form on the solid adsorbent.
20. A process for the preparation of the pharmaceutical composition
of claim 8, comprising: solvating ketamine in the fatty acid and
the co-solvent to form a solvated drug solution; adsorbing the
solvated drug solution to the solid adsorbent, thereby forming a
solvated drug solution/adsorbent; mixing the solvated drug
solution/adsorbent with the solid, water-soluble excipient, the
disintegrant, and/or the lubricant, thereby forming a blend; and
compressing the blend into the solid dosage form, wherein the
solvated drug solution is in liquid form on the solid
adsorbent.
21. A method for treating depression, suicidal ideation, pain, or
post traumatic stress disorder, or a method for effecting
anesthesia or analgesia in a patient in need thereof, comprising:
administering the pharmaceutical composition of claim 1 to the
buccal or sublingual cavity of the patient, whereby a
therapeutically effective amount of ketamine is released and is
systemically administered to the patient within 5 minutes to 15
minutes.
22. A method for treating depression, suicidal ideation, pain, or
post traumatic stress disorder, or a method for effecting
anesthesia or analgesia in a patient in need thereof, comprising:
administering the pharmaceutical composition of claim 7 to the
buccal or sublingual cavity of the patient, whereby a
therapeutically effective amount of ketamine is released and is
systemically administered to the patient within 5 minutes to 15
minutes.
23. The pharmaceutical composition of claim 1, wherein ketamine is
an R enantiomer, an S enantiomer, or a mixture thereof.
24. The pharmaceutical composition of claim 7, wherein ketamine is
an R enantiomer, an S enantiomer, or a mixture thereof.
25. A method for treating depression, suicidal ideation, pain, or
post traumatic stress disorder, or a method for effecting
anesthesia or analgesia in a patient in need thereof, comprising:
administering the pharmaceutical composition of claim 23 to the
buccal or sublingual cavity of the patient, whereby a
therapeutically effective amount of ketamine is released and is
systemically administered to the patient within 5 minutes to 15
minutes.
26. A method for treating depression, suicidal ideation, pain, or
post traumatic stress disorder, or a method for effecting
anesthesia or analgesia in a patient in need thereof, comprising:
administering the pharmaceutical composition of claim 24 to the
buccal or sublingual cavity of the patient, whereby a
therapeutically effective amount of ketamine is released and is
systemically administered to the patient within 5 minutes to 15
minutes.
Description
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical composition that
contains an ionizable pharmaceutical agent and a one or more
complementary lipophilic species where the ionizable pharmaceutical
agent and the one or more complementary lipophilic species are
formulated in a transmucosal dosage form. In certain embodiments of
the invention, the ionizable pharmaceutical agent is
hydrogen-bonded to the complementary lipophilic species, or is
ion-paired to the complementary lipophilic species, to form a
lipophilic association (LA). The pharmaceutical composition may
further contain a solvent having a dielectric constant less than
that of water, wherein the LA is solvated in the solvent to form a
solubilized LA. Examples of solvents include ethanol, ethyl
acetate, isopropyl alcohol, triacetin, triethyl citrate, tributyl
citrate, a polyethylene glycol, propylene glycol, bisabolol,
glycerin, mineral oil, ethyl oleate, fatty acid esters, squalane,
animal oils, vegetable oils, hydrogenated vegetable oils, isopropyl
myristate, isopropyl palmitate, glycofurol, terpenes, essential
oils, alcohols, polyols, or silicone fluids. The pharmaceutical
composition of the present invention may further contain a carrier,
wherein the LA, or solubilized LA, is adsorbed or absorbed to the
carrier. The carrier may be, for example a silica or a silicified
microcrystalline cellulose. The pharmaceutical composition of the
present invention may further contain a water-soluble excipient.
Such an excipient may possess a dielectric constant less than the
dielectric constant of water. Examples of water-soluble excipients
useful in the present invention include sugar, polyol, alcohol,
saccharide, polysaccharide, glycerin, propylene glycol, ethanol,
isopropyl alcohol, ethyl acetate, triacetin, triethyl citrate,
tributyl citrate, a dextrate, dextrin, dextrose, fructose,
lactitol, lactose, erythritol, maltose, maltitol, maltodextrin,
polydextrose, trehalose, mannitol polyethylene glycol, sorbitol,
sucrose or xylitol.
In the present invention, the molar ratio of lipophilic species to
ionizable pharmaceutical agent is at least about 1:1. In one
embodiment, the pharmaceutical agent possesses a basic functional
group and the lipophilic species is an acid. In the present
invention, the lipophilic species is a fatty acid, a long-chain
alkyl sulfonic acid, or a long-chain alkyl sulfuric acid. Examples
of long-chain alkyls that are found in the fatty acid, sulfonic
acid or sulfuric acid are caproic, caprylic, capric, lauric,
myristic, palmitic, stearic, arachidic, behenic, lignoceric,
myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic,
linoleic, linolenic, licanic, arachidonic and/or clupanadonic
acid.
In an alternative, the pharmaceutical agent possesses an acidic
functional group and the lipophilic species is a base. In certain
embodiments, the lipophilic species is a amine or amide, such as
cetrimide, oleamidopropyl dimethylamine, didecyldimethyl ammonium
chloride, a quaternary surfactant, cetylpyridinium chloride,
hexetidine, benzalkonium chloride or an amine or amide of caproic,
caprylic, capric, lauric, myristic, palmitic, stearic, arachidic,
behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic,
erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or
clupanadonic acid.
In certain embodiments of the present invention the carrier is
capable of forming an inclusion complex with the LA or solubilized
LA. The pharmaceutical composition of the present invention may
further contain a carrier, wherein the LA, or solubilized LA, is
adsorbed or absorbed to the carrier. The carrier may be, for
example a silica or a silicified microcrystalline cellulose.
Examples of pharmaceutical agents that may be used in embodiments
of the present invention include one or more of the following: a
antihypertensive agent, analgesic, antidepressant, opioid agonist,
anesthetic, antiarrhythmic, antiarthritic, antispasmodic, ACE
inhibitor, decongestant, antibiotic, antihistamine, anti-anginal,
diuretic, anti-hypotensive agent, anti-Parkinson agent,
bronchodilator, oxytocic agent, anti-diuretic, anti-hyperglycemic,
antineoplastic and/or immunosuppresent agent, antiemetic,
anti-infective, antifungal, antiviral, antimuscarinic, antidiabetic
agent, antiallergy agent, anxiolytic, sedative, antipsychotic, bone
modulating agent, cardiovascular agent, cholesterol lowering drug,
antimalarial, antiepileptic, antihelminthic, agent for smoking
cessation, cough suppressant, expectorant, mucolytic, nasal
decongestant, dopaminergic, gastrointestinal agent, muscle
relaxant, neuromuscular blocker, parasympathomimetic,
prostaglandin, stimulant, anorectic, thyroid or antithyroid agent,
hormone, antimigrane agent, antiobesity, and/or non-steroidal
anti-inflammatory agent. Further, the pharmaceutical agent may be
one or more of the following: dihydroergotamine, fentanyl,
sufentanil, lidocaine, alfentanil, lofentanil, carfentanil,
pentobarbital, buspirone, ergotamine, bisphosphonate, alendronic
acid, nalbuphine, bupropion, metformin, diethylcarbamazine,
tramadol, heparin or a heparin derivative, amoxicillin, gabapentin,
econazole, aspirin, prostaglandin, methylsergide, ergonovine,
endorphins, enkephalins, oxytocin, opiates, heparin and its
derivatives, clorazepic acid, barbiturate, albuterol, atropine,
scopolamine, selegiline, timolol, nicotine, cocaine, novocaine,
amphetamines, caffeine, methylphenidate, chlorpromazine, ketamine,
the R and/or S enantiomers of ketamine, ketamine active metabolites
norketaminek, dehydronorketamine, epinephrine, estropipate,
naloxone, naltrexone, furosemide, labetalol, metoprolol, nadolol,
isoproterenol, terbutaline, sumatriptan, bupivacaine, prilocalne,
loratadine, chloropheniramine, clonidine, or tetracaine. In one
example, the pharmaceutical agent is nicotine.
In certain embodiments of the present invention, the pharmaceutical
composition further contains a buffering agent, colorant,
flavoring, solvent, co-solvent, coating agent, binder, diluent,
carrier, disintegrant, glident, lubricant, opacifying agent,
humectant, granulating agent, gelling agent, polishing agent,
suspending agent, sweetening agent, anti-adherent, preservative,
emulsifying agent, antioxidant, levigating agent, plasticizer,
surfactant, tonicity agent, viscosity agent, enteric agent, enteric
coating, controlled-release agent or coating, wax, wetting agent,
thickening agent, suppository base, stiffing agent, stabilizing
agent, solubilizing agent, sequestering agent, ointment base,
oleaginous vehicle, film-forming agent, essential oil, emollient,
dissolution enhancer, dispersing agent, or cryoprotectant or
combination thereof. Examples of buffering agents include
phosphates, carbonates, tartrates, borates, citrates, acetates, and
maleates.
In the present invention, the composition may be prepared as a
buccal tablet, sublingual tablet, oral capsule, oral tablet, nasal
spray, buccal or vaginal spray, liquid/semisolid, aerosol for
nasal, buccal or pulmonary delivery, patch, lozenge, gum, lollypop,
film, strip, paper, suppository, or pessary dosage form.
In the present invention, when the pharmaceutical composition is
dissolved in water, has a pH of about physiological pH of a target
mucosal membrane.
The present invention further provides a method for transmucosal
delivery of an ionizable pharmaceutical agent The method includes
the following steps: admixing an ionizable pharmaceutical agent
with a one or more complementary lipophilic species to form a
lipophilic association (LA); formulating the LA in a transmucosal
dosage form; and administering the transmucosal dosage form to a
targeted mucosal membrane in order to deliver the pharmaceutical
agent through the mucosal membrane and into systemic circulation.
The admixing step of the present invention is performed under
conditions such that the ionizable pharmaceutical agent
hydrogen-bonds with the complementary lipophilic species, or
ionizable pharmaceutical agent ion-pairs with the complementary
lipophilic species. The method of the present invention may also
include the step of solubilizing the LA with a solvent having a
dielectric constant less than that of water to form a solubilized
LA. Examples of solvents that may be used in the present method
include ethanol, ethyl acetate, isopropyl alcohol, triacetin,
triethyl citrate, tributyl citrate, polyethylene glycol, propylene
glycol, bisabolol, glycerin, mineral oil, ethyl oleate, fatty acid
esters, squalane, animal oil, vegetable oil, hydrogenated vegetable
oil, isopropyl myristate, isopropyl palmitate, glycofurol, terpene,
essential oil, alcohol, polyol, and/or a silicone fluid.
The transmucosal dosage form may further include a carrier, wherein
the LA, or solubilized LA, is adsorbed or absorbed to the carrier.
Examples of carriers include silica or silicified microcrystalline
cellulose. The transmucosal dosage form may further include a
water-soluble excipient. The excipient may possess a dielectric
constant less than the dielectric constant of water. Examples of
suitable water-soluble excipients are sugars, polyols, alcohols,
saccharides, polysaccharides, glycerin, propylene glycol, ethanol,
isopropyl alcohol, ethyl acetate, triacetin, triethyl citrate,
tributyl citrate, dextrates, dextrins, dextrose, fructose,
lactitol, lactose, erythritol, maltose, maltitol, maltodextrins,
polydextroses, trehalose, mannitol, polyethylene glycols, sorbitol,
sucrose and/or xylitol.
In the present invention, the molar ratio of lipophilic species to
ionizable pharmaceutical agent is at least about 1:1. In one
embodiment, the pharmaceutical agent possesses a basic functional
group and the lipophilic species is an acid. In the present
invention, the lipophilic species is a fatty acid, a long-chain
alkyl sulfonic acid, or a long-chain alkyl sulfuric acid. Examples
of long-chain alkyls that are found in the fatty acid, sulfonic
acid or sulfuric acid are caproic, caprylic, capric, lauric,
myristic, palmitic, stearic, arachidic, behenic, lignoceric,
myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic,
linoleic, linolenic, licanic, arachidonic and/or clupanadonic
acid.
In an alternative, the pharmaceutical agent possesses an acidic
functional group and the lipophilic species is a base. In certain
embodiments, the lipophilic species is a amine or amide, such as
cetrimide, oleamidopropyl dimethylamine, didecyldimethyl ammonium
chloride, a quaternary surfactant, cetylpyridinium chloride,
hexetidine, benzalkonium chloride or an amine or amide of caproic,
caprylic, capric, lauric, myristic, palmitic, stearic, arachidic,
behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic,
erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or
clupanadonic acid.
In certain embodiments of the present invention the carrier is
capable of forming an inclusion complex with the LA or solubilized
LA. The pharmaceutical composition of the present invention may
further contain a carrier, wherein the LA, or solubilized LA, is
adsorbed or absorbed to the carrier. The carrier may be, for
example a silica or a silicified microcrystalline cellulose.
In certain embodiments of the present invention, the pharmaceutical
agent may be one or more of the following: a antihypertensive
agent, analgesic, antidepressant, opioid agonist, anesthetic,
antiarrhythmic, antiarthritic, antispasmodic, ACE inhibitor,
decongestant, antibiotic, antihistamine, anti-anginal, diuretic,
anti-hypotensive agents, anti-Parkinson agent, bronchodilator,
oxytocic agent, anti-diuretic, anti-hyperglycemic, antineoplastic
and/or immunosuppresent agent, antiemetic, anti-infective,
antifungal, antiviral, antimuscarinic, antidiabetic agent,
antiallergy agent, anxiolytic, sedative, antipsychotic, bone
modulating agent, cardiovascular agent, cholesterol lowering drug,
antimalarial, antiepileptic, antihelminthic, agent for smoking
cessation, cough suppressant, expectorant, mucolytic, nasal
decongestant, dopaminergic, gastrointestinal agent, muscle
relaxant, neuromuscular blocker, parasympathomimetic,
prostaglandin, stimulant, anorectic, thyroid or antithyroid agent,
hormone, antimigrane agent, antiobesity, and/or non-steroidal
anti-inflammatory agent. Further, the pharmaceutical agent may be
one or more of the following: dihydroergotamine, fentanyl,
sufentanil, lidocaine, alfentanil, lofentanil, carfentanil,
pentobarbital, buspirone, ergotamine, bisphosphonate, alendronic
acid, nalbuphine, bupropion, metformin, diethylcarbamazine,
tramadol, heparin or a heparin derivative, amoxicillin, gabapentin,
econazole, aspirin, prostaglandin, methylsergide, ergonovine,
endorphins, enkephalins, oxytocin, opiates, barbiturate, albuterol,
atropine, scopolamine, selegiline, timolol, nicotine, cocaine,
novocaine, amphetamines, caffeine, heparin and its derivatives,
clorazepic acid, methylphenidate, chlorpromazine, ketamine,
epinephrine, estropipate, naloxone, naltrexone, furosemide,
labetalol, metoprolol, nadolol, isoproterenol, terbutaline,
sumatriptan, bupivacaine, prilocalne, loratadine,
chloropheniramine, clonidine, or tetracaine. In one embodiment the
pharmaceutical agent is ketamine. In some embodiments, the ketamine
is the R enantiomer, the S enantiomer, or a mixture of both.
In embodiments of the present invention, the transmucosal dosage
form may additionally contain a buffering agent, colorant,
flavoring, solvent, co-solvent, coating agent, binder, diluent,
carrier, disintegrant, glident, lubricant, opacifying agent,
humectant, granulating agent, gelling agent, polishing agent,
suspending agent, sweetening agent, anti-adherent, preservative,
emulsifying agent, antioxidant, levigating agent, plasticizer,
surfactant, tonicity agent, viscosity agent, enteric agent, enteric
coating, controlled-release agent or coating, wax, wetting agent,
thickening agent, suppository base, stiffing agent, stabilizing
agent, solubilizing agent, sequestering agent, ointment base,
oleaginous vehicle, film-forming agent, essential oil, emollient,
dissolution enhancer, dispersing agent, or cryoprotectant or
combination thereof.
In the method of the present invention, the buffering agent may be
a phosphate, carbonate, tartrate, borate, citrate, acetate, and/or
maleate.
The target mucosal tissue may be oral mucosa, esophagus,
gastrointestinal tract, lungs, rectum, sinuses, eye, urinary tract
or a lining of a female reproductive organ. In the method of the
present invention, the ionizable pharmaceutical agent is delivered
rapidly across the mucosal membrane. For example, the ionizable
pharmaceutical agent is delivered across the mucosal membrane in
about 10 minutes or less.
In the present invention, the pharmaceutical composition when
dissolved in water has a pH near the physiological pH of the target
mucosal membrane.
The present invention also provides a method of manufacturing a
transmucosal pharmaceutical unit dosage forms described above. The
manufacturing method involves the following steps: admixing an
ionizable pharmaceutical agent with a one or more complementary
lipophilic species to form a lipophilic association (LA); and
formulating the LA into a transmucosal unit dosage form. The
admixing is performed under conditions such that the ionizable
pharmaceutical agent hydrogen-bonds, or ion-pairs, with the
complementary lipophilic species. The method may further involve
admixing an adsorbent, a water-soluble excipient, a disintegrant
and a lubricant. In one example, the water soluble excipient is
mannitol, the disintegrant is sodium starch glycolate and the
lubricant is sodium stearyl fumarate.
In certain embodiments, the LA is formed into a buccal tablet,
sublingual tablet, oral capsule, oral tablet, nasal spray, buccal
or vaginal spray, liquid/semisolid, aerosol for nasal, buccal or
pulmonary delivery, patch, lozenge, gum, lollypop, film, strip,
paper, suppository, or pessary dosage form. The dosage forms may be
manufactured by direct tablet compression, wet or dry granulation,
dry powder blends, molding, spray-congealing, powder layering,
tableting, encapsulating, spray-drying, spheronization, triturates,
lyophilization, freeze drying, co-melt, microencapsulation,
troching, pelleting, aerosolizing, liquid or semisolid processes
manufacturing.
The present manufacturing method may further involve solubilizing
the LA with a solvent having a dielectric constant less than that
of water to form a solubilized LA. Examples of solvents include one
or more of the following: ethanol, ethyl acetate, isopropyl
alcohol, triacetin, triethyl citrate, tributyl citrate,
polyethylene glycols, propylene glycol, bisabolol, glycerin,
mineral oil, ethyl oleate, fatty acid esters, squalane, animal
oils, vegetable oils, hydrogenated vegetable oils, isopropyl
myristate, isopropyl palmitate, glycofurol, terpenes, essential
oils, alcohols, polyols, and/or silicone fluids.
The present manufacturing method may further involve admixing a
carrier with the LA (or solubilized LA), wherein the LA (or
solubilized LA) is adsorbed or absorbed to the carrier. Examples of
carriers include a silica or a silicified microcrystalline
cellulose. In the present invention, the transmucosal dosage form
may further contain a water-soluble excipient. Such a water-soluble
excipient may possess a dielectric constant less than the
dielectric constant of water. Examples of water-soluble excipients
include a sugar, a polyol, an alcohol a saccharide, a
polysaccharide, glycerin, propylene glycol, ethanol, isopropyl
alcohol, ethyl acetate, triacetin, triethyl citrate, tributyl
citrate, a dextrate, a dextrin, dextrose, fructose, lactitol,
lactose, erythritol, maltose, maltitol, a maltodextrin, a
polydextrose, trehalose, mannitol, a polyethylene glycol, sorbitol,
sucrose and/or xylitol. In the present invention, the molar ratio
of lipophilic species to ionizable pharmaceutical agent is at least
about 1:1. In one embodiment, the pharmaceutical agent possesses a
basic functional group and the lipophilic species is an acid. In
the present invention, the lipophilic species is a fatty acid, a
long-chain alkyl sulfonic acid, or a long-chain alkyl sulfuric
acid. Examples of long-chain alkyls that are found in the fatty
acid, sulfonic acid or sulfuric acid are caproic, caprylic, capric,
lauric, myristic, palmitic, stearic, arachidic, behenic,
lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic,
ricinoleic, linoleic, linolenic, licanic, arachidonic and/or
clupanadonic acid.
In certain embodiments of the present method, the pharmaceutical
agent possesses an acidic functional group and the lipophilic
species is a base. In certain embodiments, the lipophilic species
is a amine or amide, such as cetrimide, oleamidopropyl
dimethylamine, didecyldimethyl ammonium chloride, a quaternary
surfactant, cetylpyridinium chloride, hexetidine, benzalkonium
chloride or an amine or amide of caproic, caprylic, capric, lauric,
myristic, palmitic, stearic, arachidic, behenic, lignoceric,
myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic,
linoleic, linolenic, licanic, arachidonic and/or clupanadonic
acid.
In the present method, the carrier is capable of forming an
inclusion complex with the LA or solubilized LA. The pharmaceutical
composition of the present invention may further contain a carrier,
wherein the LA, or solubilized LA, is adsorbed or absorbed to the
carrier. The carrier may be, for example a silica or a silicified
microcrystalline cellulose.
Examples of pharmaceutical agents that may be used in the present
method include one or more of the following: a antihypertensive
agent, analgesic, antidepressant, opioid agonist, anesthetic,
antiarrhythmic, antiarthritic, antispasmodic, ACE inhibitor,
decongestant, antibiotic, antihistamine, anti-anginal, diuretic,
anti-hypotensive agents, anti-Parkinson agent, bronchodilator,
oxytocic agent, anti-diuretic, anti-hyperglycemic, antineoplastic
and/or immunosuppresent agent, antiemetic, anti-infective,
antifungal, antiviral, antimuscarinic, antidiabetic agent,
antiallergy agent, anxiolytic, sedative, antipsychotic, bone
modulating agent, cardiovascular agent, cholesterol lowering drug,
antimalarial, antiepileptic, antihelminthic, agent for smoking
cessation, cough suppressant, expectorant, mucolytic, nasal
decongestant, dopaminergic, gastrointestinal agent, muscle
relaxant, neuromuscular blocker, parasympathomimetic,
prostaglandin, stimulant, anorectic, thyroid or antithyroid agent,
hormone, antimigrane agent, antiobesity, and/or non-steroidal
anti-inflammatory agent. Further examples of pharmaceutical agents
that may be used in the present method include one or more of the
following: dihydroergotamine, fentanyl, sufentanil, lidocaine,
alfentanil, lofentanil, carfentanil, pentobarbital, buspirone,
ergotamine, bisphosphonate, alendronic acid, nalbuphine, bupropion,
metformin, diethylcarbamazine, tramadol, heparin or a heparin
derivative, amoxicillin, gabapentin, econazole, aspirin,
prostaglandin, methylsergide, ergonovine, endorphins, enkephalins,
oxytocin, opiates, barbiturate, albuterol, atropine, scopolamine,
selegiline, timolol, nicotine, cocaine, novocaine, amphetamines,
caffeine, heparin and its derivatives, clorazepic acid,
methylphenidate, chlorpromazine, ketamine, epinephrine,
estropipate, naloxone, naltrexone, furosemide, labetalol,
metoprolol, nadolol, isoproterenol, terbutaline, sumatriptan,
bupivacaine, prilocalne, loratadine, chloropheniramine, clonidine,
or tetracaine. In one embodiment, the pharmaceutical agent is
nicotine.
In certain embodiments of the present method, the process involves
admixing with the LA or solubilized LA a buffering agent, colorant,
flavoring, solvent, co-solvent, coating agent, binder, diluent,
carrier, disintegrant, glident, lubricant, opacifying agent,
humectant, granulating agent, gelling agent, polishing agent,
suspending agent, sweetening agent, anti-adherent, preservative,
emulsifying agent, antioxidant, levigating agent, plasticizer,
surfactant, tonicity agent, viscosity agent, enteric agent, enteric
coating, controlled-release agent or coating, wax, wetting agent,
thickening agent, suppository base, stiffing agent, stabilizing
agent, solubilizing agent, sequestering agent, ointment base,
oleaginous vehicle, film-forming agent, essential oil, emollient,
dissolution enhancer, dispersing agent, or cryoprotectant or
mixture thereof.
In certain embodiments of the present invention, the buffering
agent is a phosphate, carbonate, tartrate, borate, citrate,
acetate, and/or maleate.
In certain embodiments of the present invention, the pharmaceutical
composition, when solubilzed in water, has a pH of about
physiological pH of a target mucosal membrane.
Further, the present invention provides pharmaceutical products
prepared by the methods of manufacture described above.
The present invention also provides a method of treating a patient
in need thereof by administering a pharmaceutical composition
containing an ionizable pharmaceutical agent and a one or more
complementary lipophilic species, wherein the ionizable
pharmaceutical agent and the one or more complementary lipophilic
species are formulated in a transmucosal dosage form, and wherein
the pharmaceutical composition is administered as a bolus release
across a mucosal membrane. In an embodiment of this method, the
ionizable pharmaceutical agent is delivered rapidly across the
mucosal membrane, such as in about 10 minutes or less. In some
embodiments, the ionizable pharmaceutical agent is ketamine, its R
and/or S enantiomers, and/or its active metabolites, norketamine
and/or dehydronorketamine. In one embodiment, the pharmaceutical
composition is has a pH of about physiological pH of a target
mucosal membrane. For example, in one embodiment nicotine is
transmucosally delivered sublingually at a pH between about 5.5 and
about 7.5.
In some embodiments, the present disclosure provides a method for
treating depression, suicidal ideation, pain, anesthesia, analgesia
post traumatic shock disorder, and other central nervous systems
disease states for which ketamine is an effective therapeutic, in a
patient in need thereof, comprising: administering the
pharmaceutical composition of according to the disclosure to the
buccal or sublingual cavity of the patient, whereby a
therapeutically effective amount of ketamine is released and is
systemically administered to the patient within 5 minutes to 15
minutes.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic showing a method of manufacture of a nicotine
sublingual/buccal tablet according to the invention.
FIG. 2 is a graph showing a dissolution profile of nicotine as
delivered by a formulation according to the invention and compared
to a dissolution profile of prior-art formulations.
FIG. 3 is a schematic showing a method of manufacture of an
epinephrine sublingual/buccal tablet according to the
invention.
FIG. 4 is a schematic showing a method of manufacture of a fentanyl
sublingual/buccal tablet according to the invention.
FIG. 5 is a schematic showing a method of manufacture of alendronic
acid sublingual/buccal tablet according to the invention.
FIG. 6 is a schematic showing a method of manufacture of a
clorazepic acid sublingual/buccal tablet according to the
invention.
FIG. 7 is a graph showing a dissolution profile of nicotine as
delivered by a formulation according to the invention and compared
to a dissolution profile of prior-art formulations.
FIG. 8 is a graph of a sublingual nicotine formulation mucosal
permeation rate compared to a prior art formulation.
FIG. 9 is a graph of a sublingual nicotine formulation plasma level
over time compared to prior art formulations.
FIG. 10 is a graph comparing vital signs over time as a function of
nicotine plasma concentration.
DESCRIPTION OF THE INVENTION
The invention provides a composition and a method for delivery of a
pharmaceutical agent. In particular, the invention provides a
pharmaceutical formulation for enhanced transmucosal delivery of an
ionizable pharmaceutically active substance at or near
physiological pH. Transmucosal delivery includes the oral mucosa,
esophagus, gastrointestinal tract including the stomach and colon,
lungs, rectum, sinuses, eyes, urinary tract and the linings of the
female reproductive organs. The physiological pH of these various
membranes varies considerably. The physiological pH of the
gastrointestinal tract increases along its length from about pH 1
in the stomach to pH 8 in the colon. Saliva has a pH around 6.8.
The pH of nasal fluids range from about pH 5.5 to 6.5. The pH of
the vagina is around 4.5. The invention is designed to provide
transmucosal delivery in the pH range specific to the target
mucosal tissue to avoid local irritation. Transmucosal absorption,
as embodied in this invention, is not dependent on pH. This is
unlike the prior art that requires that the pH be adjusted,
typically by the use of buffers, to insure that the ionizable
pharmaceutical agent is predominately in its freebase or free acid
form for optimal transmucosal delivery. Transmucosal delivery of
the ionizable pharmaceutical, as embodied in this invention, only
requires the development of a hydration and dielectric gradient.
The present invention comprises a pharmaceutical formulation that
is capable of rapidly delivering a pharmaceutical agent into the
mucosal tissue or the through the mucosal tissue into the
circulatory system. For example the pharmaceutical agent may be
absorbed through the oral mucosal tissue for systemic delivery.
The invention further provides a process for the production, and a
method of use, of such a formulation. More specifically, the
invention provides a high thermodynamic activity lipophilic
association (LA) of an ionizable pharmaceutical agent paired with a
lipophilic agent having ionic character opposite to that of the
pharmaceutical agent, such that the association is a liquid or is
solubilized in a lower-than-water dielectric solvent. As used
herein, the term "high thermodynamic activity" means that the
lipophilic association or lipophilic association solvate is in a
liquid state at room temperature. The LA being a liquid state, or
solubilized, is at high thermodynamic activity such that drug
dissolution is no longer rate limiting to transmucosal absorption.
Further, the invention provides for formulating the high
thermodynamic activity LA into a lower-than-water dielectric dosage
form, which upon hydration results in an increasingly higher
dielectric gradient. This provides the driving force for enhanced
delivery of the lipophilized ionizable pharmaceutical agent through
the mucus and into systemic circulation at or near physiological
pH.
The invention provides, inter alia, a process for making a
transmucosal drug delivery system for an ionizable pharmaceutical
agent by use of a lipophilic species having a charge, when ionized,
opposite that of the ionized pharmaceutical agent. It is the
applicants present understanding that a lipophilic association
according to the invention may be, for example, prepared according
to the outline below. That is, for a basic ionizable functional
group on an ionizable pharmaceutical agent that is not ionized
(deprotonated), the corresponding acidic lipophilic species is also
not ionized (protonated). For a basic ionizable group on a
ionizable pharmaceutical agent that is ionized (protonated), the
corresponding acidic lipophilic species is also ionized
(deprotonated). In like manner, for an acid ionizable functional
group on an ionizable pharmaceutical agent that is not ionized
(protonated), the corresponding basic lipophilic species is also
not ionized (deprotonated). For a acid ionizable group on a
ionizable pharmaceutical agent that is ionized (deprotonated), the
corresponding basic lipophilic species is also ionized
(protonated).
For a basic drug, a lipophilic species according to the invention
is, for example, fatty acid or another lipophilic species. For a
basic drug, a lipophilic species according to the invention may,
for example, be one or more of the following fatty acids, or
long-chain alkyl sulfonic acids, or a long-chain alkyl sulfuric
acids: caproic, caprylic, capric, lauric, myristic, palmitic,
stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic,
oleic, gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic,
arachidonic and/or clupanadonic.
For an acidic drug, a lipophilic species according to the invention
is, for example, a fatty amine or another lipophilic species. For
an acidic drug, a lipophilic species according to the invention is
cetrimide, oleamidopropyl dimethylamine, didecyldimethyl ammonium
chloride, quaternary surfactants, cetylpyridinium chloride,
hexetidine, benzalkonium chloride and the following fatty amines
and acid amides: caproic, caprylic, capric, lauric, myristic,
palmitic, stearic, arachidic, behenic, lignoceric, myristoleic,
palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic,
linolenic, licanic, arachidonic and/or clupanadonic.
A formulation according to the invention contains an ionizable drug
and an oppositely charged lipophilic species, to form the
lipophilic association. The LA may require, if not already at a
high thermodynamic activity liquid state, the use of
lower-than-water dielectric solvent in order to prepare a
LA-solvate that has high thermodynamic activity. Examples of
appropriate lower-than-water dielectric solvents include ethanol,
ethyl acetate, isopropyl alcohol, triacetin, triethyl citrate,
tributyl citrate, polyethylene glycols, propylene glycol,
bisabolol, glycerin, mineral oil, ethyl oleate, fatty acid esters,
squalane, animal oils, vegetable oils, hydrogenated vegetable oils,
isopropyl myristate, isopropyl palmitate, glycofurol, terpenes,
essential oils, alcohols, polyols, or silicone fluids.
A formulation according to the invention contains an ionizable
drug, an oppositely charged lipophilic species, and an excipient,
for example, a water-soluble excipient, to lower the local delivery
area's dielectric constant, which is more favorable for association
between the pharmaceutical agent and the lipophilic species in this
lipophilic association. Examples of appropriate water-soluble
excipients include a sugar, a polyol, an alcohol, a saccharide, a
polysaccharide, glycerin, propylene glycol, ethanol, isopropyl
alcohol, ethyl acetate, triacetin, triethyl citrate, tributyl
citrate, a dextrate, dextrin, dextrose, fructose, lactitol,
lactose, erythritol, maltose, maltitol, maltodextrin, polydextrose,
trehalose, mannitol, polyethylene glycol, sorbitol, sucrose and/or
xylitol.
While the invention is not to be limited by theory, it is the
applicant's understanding that, as water from the local delivery
environment hydrates the high thermodynamic activity, lipophilic
association, lower-than-water dielectric formulation according to
the invention, a hydration and dielectric gradient is formed that
provides the driving force for delivery of the lipophilized
ionizable pharmaceutical agent through the mucosa and into systemic
circulation.
Surprisingly, it has been found that, in one embodiment, i.e., a
nicotine sublingual/buccal tablet, a tablet containing a LA
prepared with nicotine and oleic acid at a 1:1 molar ratio is
effective in providing a rapid, bolus dose of nicotine after
sublingual administration. In the art, to enhance delivery, many
formulations require a molar ratio of oppositely charged species to
active pharmaceutical agent of 50:1 or greater (M. Trotta, E.
Urazio, E. Peira and C. Pulitano, "Influence of ion pairing on
topical delivery of retinoic acid from microemulsions", J. Control
Release, 2003, Vol. 86, pp 315-321).
Further, in a nicotine sublingual/buccal tablet embodiment of the
invention prepared with nicotine and oleic acid, the LA is a liquid
with a pH in water of about 5.5 to 7.5, depending on the amount of
the oleic acid present. Delivery is as rapid, and possibly more
rapid, at lower pHs, the acidity being determined by any excess
oleic acid over that needed for formation of the LA. However,
excessive acidity is not necessary. Lower-than-physiological pHs
would result if excessive amounts of oleic acid were needed for
transmucosal delivery of the ionizable pharmaceutical agent. This
attests to the efficiency of the invention. Further, at the pH
range of this delivery system, nicotine predominately in the
ionized form. Such efficient delivery at a pH where nicotine is
ionized is surprising, because ionized pharmaceutical agents
typically have very poor transmucosal delivery (Beckett and Hossie:
Buccal Absorption of Drugs, in Handbook of Experimental
Pharmacology, ed. B. B. Brodie and J. R. Gillette; Springer-Verlag,
Berlin (1971), Ch. 3, and H. R. Leipold and E. Quadros: Nicotine
Permeation Through Buccal Cultures, in Proceed. Intern. Symp.
Control. Rel. Bioact. Mater., Controlled Release Society, 20
(1993), 242-243).
When a nicotine formulation is prepared according to the present
invention, a rapid, bolus delivery of nicotine results from
sublingual administration of the formulation in the physiological
pH range of saliva, where nicotine's predominant form is ionized.
This is among the advantages that a formulation according to the
invention possesses over other known formulations. In general,
transmucosal and transdermal drug delivery systems for ionizable
pharmaceutical agents resort to using the free-base or free-acid
form of the drug to obtain the desired level of drug permeation.
Delivery of the free-base or free-acid form can cause the local
delivery area's pH to be far outside the normal range of the local
delivery area's customary physiological pH. This pH perturbation
can result in local tissue irritation and cell death. By virtue of
the inherent capacity of a formulation according to the invention
to deliver ionizable pharmaceutical agents at or near physiological
pH, delivery of a ionizable pharmaceutical agent according to the
invention significantly reduces local tissue irritation and cell
death when compared with delivery of other formulations. For
example, delivery of nicotine free-base could cause a transient
increase in local delivery area pH to 10 or above, a pH known in
the art to be caustic. Indeed, one of the side effects of the
sublingual nicotine tablet MICROTAB.TM. is an oral ulcer in the
delivery area.
Transmucosal drug delivery according to the invention includes
inter alia certain preparative steps. According to the invention,
an ionizable pharmaceutical agent is prepared into a lipophilic
association (LA) by pairing with a lipophilic species that bears,
when ionized, an opposite charge to that of the ionized
pharmaceutical agent. In selecting the lipophilic species, efforts
are made to ensure that the LA is at high thermodynamic activity,
i.e. produces a liquid at room temperature. If this is not possible
the LA is solvated in a lower-than-water dielectric solvent to
produce a high activity, liquid LA-solvate. Further, the LA or
LA-solvate is formulated so that when placed in water results in a
solution pH at or near physiological pH of the targeted mucosal
tissue. The LA or LA-solvate is formulated into a dosage form that
on contact with water results in an increasing hydration and
dielectric gradient, providing a driving force for transmucosal
delivery of the lipophilized ionizable pharmaceutical agent. This
can be accomplished by including a water-soluble excipient that has
a lower dielectric constant than water or that, when solubilized in
water, lowers the solution's dielectric constant from that of
water.
The invention possesses a number of advantages over known
formulations. The invention's lipophilic, high thermodynamic
activity LA formulations provide for improved transmucosal drug
absorption. First, dissolution of the pharmaceutical agent is no
longer rate limiting to transmucosal absorption, i.e. the ionizable
pharmaceutical agent is already dissolved being a liquid or in
solution as the LA or LA-solvate respectively. Second, being in a
liquid state the LA is at high molecular thermodynamic activity.
Third, due to the lipophilic species used in the formation of the
LA, it has greater affinity to lower-than-water dielectric
environments such as cell membranes. The combination of a high
thermodynamic activity liquid state, with the drug being in
solution so as dissolution is not rate limiting, and the
lipophilicity of the LA, driven by development of an increasing
hydration and dielectric gradient as water enters the
lower-than-water dielectric dosage form, provides optimal
conditions for delivery of an ionizable pharmaceutical agent
through the mucosa and into systemic circulation. A further
advantage that the invention provides is transmucosal drug delivery
at or near physiological pH. Previously known transmucosal delivery
systems for ionizable pharmaceutical agents resort to using the
free-base or free-acid forms of the drug substance to provide
transmucosal drug permeation. In such cases the local delivery area
pH can be far outside the range of physiological pH, resulting in
local tissue irritation and cell death.
A formulation according to the invention is embodied in any of a
wide variety of different dosage forms, such as buccal tablet,
sublingual tablet, oral capsule, oral tablet, nasal spray, buccal
or vaginal spray, liquid/semisolid, aerosol for nasal, buccal or
pulmonary delivery, patch, lozenge, gum, lollypop, film, strip,
paper, suppository, pessary or other dosage forms using
manufacturing techniques familiar to one versed in the art of
formulating and processing pharmaceutical dosage forms. A
manufacturing technique according to the invention includes any of
the processes of direct tablet compression, wet or dry granulation,
co-melt, dry powder blends, molding, spray-congealing, powder
layering, tableting, encapsulating, spray-drying, spheronization,
triturates, lyophilization, freeze drying, microencapsulation,
troching, pelleting, aerosolizing, liquid or semisolid
preparation.
In one embodiment of the present invention, a process of direct
powder blends is used to create a solid dosage form. The process of
direct powder blends can be outlined as weighing and blending of
several ingredients and either encapsulating or compressing the
blend into tablet. This is the process that is used in the examples
given herein as embodiments.
In one embodiment of the present invention, a process of wet
granulation is used to create a solid dosage form. The process of
wet granulation can be outlined as several steps: weighing and
blending of several ingredients in the presence of solvent(s),
drying the mixture into a solid, and milling the solid to proper
size.
In the weighing and blending step of wet granulation, proper
amounts of drug and lipophilic species and solvent are mixed
thoroughly. Additional ingredients may be added to facilitate the
mixing of the ingredients. The end result of this step is a finely
blended mixture in which the drug and the lipophilic agent are
mixed.
In another embodiment of the present invention, a process of
co-melting is used. In this process, the LA is heated with a low
melting water-soluble excipient, e.g. polyethylene glycol 6000. In
its melted state, the excipient can act as a solvent into which the
LA is dissolved or dispersed. The mixture of LA and excipient is
then cooled and solidified. The solid solution of LA and excipient
will be further processed into compressible powder. Other
ingredients may also be added to the co-melted powder to complete
the drug formulation.
In yet another embodiment of the present invention, a process of
freeze-drying is used. In this process, the LA is dissolved or
dispersed in water with a water-soluble powder, e.g. mannitol. The
solution is quickly frozen. The frozen solid is then put into a
vacuum chamber where the water is removed from the solid via
sublimation. The resulting powder is a solid carrier of LA on a
water-soluble excipient.
In yet another embodiment of the present invention, a process of
spray drying is used. In this process, the LA is dissolved or
dispersed in a solvent with an excipient. The solution or
dispersion is then sprayed into a chamber. The solvent is
evaporated while the droplets are in the air. The result is a fine
powder consisting of the LA on carrier excipient.
There are many other processes for making the final dosage form.
The selection of the process will mainly depend on the LA or
LA-solvate and the final dosage form most suitable for treatment of
the diseased state.
One embodiment of the invention provides a rapid, bolus dose of an
ionizable pharmaceutical agent transmucosally and is formulated as
liquid/semisolid or as a rapidly dissolving dosage form. Further
embodiments of the invention provides sustained, delayed and
pulsatile drug delivery. In the case of rapid bolus administration,
the dosage from dissolves and releases the ionizable pharmaceutical
agent relatively quickly, such as within 30 minutes. A sustained
release formulation provides a slower delivery of the ionizable
pharmaceutical agent from the dosage form. A delayed release dosage
form provides a period of time after administration in which no
drug delivery occurs, e.g., enteric or colonic delivery systems. A
pulsatile release formulation provides repeated bolus delivery of
the ionizable pharmaceutical agent from the dosage form. Given the
description of the invention contained in this application, it will
be apparent to one skilled in the art how to prepare any such
dosage form.
To treat a subject, the formulation, is administered by oral,
sublingual, buccal, vaginal, rectal, pulmonary, ophthalmic, or
intranasal route. Formulations will contain an effective amount of
the active ingredient in a LA or LA-solvate. The effective amount
is sufficient to treat a disease state in the target mammal. The
effective amount is readily determined by one skilled in the art.
The active ingredient may typically range from about 1% to about
95% (w/w) of the composition, or even higher or lower if
appropriate. The quantity to be administered depends upon factors
such as the age, weight and physical condition of the animal or the
human subject. The quantity also depends upon the degree of
activity desired. Effective dosages can be readily established by
one of ordinary skill in the art through routine trials
establishing dose response curves. The subject is treated by
administration of the formulation in one or more doses. Multiple
doses may be administered as required.
Intranasal formulations may include vehicles that neither cause
irritation to the nasal mucosa nor significantly disturb ciliary
function. Diluents such as propylene glycol or polyethylene glycol
or other known substances can be employed with the subject
invention. The nasal formulations may also contain preservatives
such as, but not limited to, chlorobutanol and benzalkonium
chloride.
Oral preparations may be in the form of, for example, aqueous
solution using excipients to lower dielectric constant to less than
water or oily suspension, solutions, emulsions, syrups or elixirs,
or may be presented dry in tablet or capsule form or a product for
reconstitution with water or other suitable vehicle before use.
Such liquid preparations may contain conventional additives such as
suspending agents, emulsifying agents, lower-than-water dielectric
excipients, non-aqueous vehicles (which may include edible oils),
or preservative.
Ionizable Pharmaceutical Agent. A pharmaceutical agent according to
the invention is an ionizable drug substance used for diagnosis,
prevention, control, or treatment of a physiological, pathological
or psychological condition. It is understood that a considerable
variety of drug classes and specific drugs are useful as a
pharmaceutical agent according to the invention. A pharmaceutical
agent according to the invention may be, for example, a member of
any of the following classes of drugs: antihypertensive agents,
analgesics, antidepressants, opioid agonist, anesthetics,
antiarrhythmic, antiarthritics, antispasmodics, ACE inhibitors,
decongestants, antibiotics, antihistamines, anti-anginal,
diuretics, anti-hypotensive agents, anti-Parkinson agents,
bronchodilators, oxytocic agents, anti-diuretics,
anti-hyperglycemics, antineoplastics and immunosuppresents agents,
antiemetics, anti-infectives, antifungals, antivirals,
antimuscarinics, antidiabetic agents, antiallergy agents,
anxiolytics, sedatives, antipsychotics, bone modulating agents,
cardiovascular agents, cholesterol lowering drugs, antimalarials,
antiepileptics, antihelmintics, agents for smoking cessation, cough
suppressants, expectorants, mucolytics, nasal decongestants,
dopaminergics, gastrointestinal agents, muscle relaxants,
neuromuscular blockers, parasympathomimetics, prostaglandins,
stimulants, anorectics, thyroid and antithyroid agents, hormones,
antimigrane agents, antiobesity, and non-steroidal
anti-inflammatory agents. In an embodiment, a pharmaceutical agent
according to the invention is a dihydroergotamine, fentanyl,
sufentanil, lidocaine, alfentanil, lofentanil, carfentanil,
pentobarbital, buspirone, ergotamine, bisphosphonates, alendronic
acid, nalbuphine, bupropion, metformin, diethylcarbamazine,
tramadol, amoxicillian, gabapentin, econazole, aspirin, heparin and
its derivatives, prostaglandins, methylsergide, ergonovine,
endorphin, enkephalins, oxytocin, opiate, barbiturates, albuterol,
atropine, scopolamine, selegiline, timolol, nicotine, cocaine,
novocaine, amphetamine, caffeine, clorazepic acid, methylphenidate,
chlorpromazine, ketamine, epinephrine, estropipate, naloxone,
naltrexone, furosemide, labetalol, metoprolol, nadolol,
isoproterenol, terbutaline, sumatriptan, bupivacaine, prilocalne,
loratadine, chloropheniramine, clonidine, and/or tetracaine.
Lipophilic Species. A lipophilic species according to the invention
possesses, when ionized, a charge opposite that of an ionizable
pharmaceutical agent according to the invention. A lipophilic
species according to the invention combines with the pharmaceutical
agent to form a high thermodynamic activity, low dielectric
constant, lipophilic association. In an embodiment, a
pharmaceutical agent and a lipophilic species are mixed together in
about a 1:1 molar ratio. In a further embodiment, an ionizable
pharmaceutical agent having more than one ionizable group may
require mixing with an equal molar ratio of oppositely charged
lipophilic species for each ionizable group. In yet a further
embodiment, a pharmaceutical agent itself bears oppositely charged
ionizable groups, such as in the case of a peptide or a protein,
and may be mixed with both anionic and cationic lipophilic species.
In a particular embodiment, a molar excess of a lipophilic species
is mixed with the ionizable pharmaceutical agent, lowering the
dielectric constant and improving solubility of the LA.
For a drug having basic functional groups, a lipophilic species
according to the invention is an anion (when ionized), for example,
a fatty acid. For drugs with basic functional groups, a lipophilic
species according to the invention is one or more of the following
fatty acids, long-chain alkyl sulfonic acids, or long-chain alkyl
sulfuric acids: caproic, caprylic, capric, lauric, myristic,
palmitic, stearic, arachidic, behenic, lignoceric, myristoleic,
palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic,
linolenic, licanic, arachidonic and/or clupanadonic. For drugs with
acidic functional groups, a lipophilic species according to the
invention is a cation (when ionized), for example, fatty amines.
For drugs with acidic functional groups, a lipophilic species
according to the invention is one or more of the following:
cetrimide, oleamidopropyl dimethylamine, didecyldimethyl ammonium
chloride, quaternary surfactants, cetylpyridinium chloride,
hexetidine, benzalkonium chloride, and/or one or more of the
following fatty amines and acid amides: caproic, caprylic, capric,
lauric, myristic, palmitic, stearic, arachidic, behenic,
lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic,
ricinoleic, linoleic, linolenic, licanic, arachidonic and/or
clupanadonic. Drugs with multiple functional groups would require
mixtures of these lipophilic species.
LA Solvent. A lipophilic species according to the invention is
mixed with a pharmaceutical agent according to the invention to
form a high thermodynamic activity, low dielectric, lipophilic LA.
In an embodiment, the LA thus formed is a liquid and therefore is
already at high activity. In a further embodiment, the LA is
solubilized in order to attain a high activity thermodynamic state,
i.e., a liquid state at room temperature. In a particular
embodiment, a formulation according to the invention contains a
molar excess of one or more lipophilic species for solubilizing and
providing a low dielectric liquid environment for the LA. In a
further particular embodiment, a formulation according to the
invention contains a lower-than-water dielectric solvent other than
a lipophilic species. In an embodiment, a lower-than-water
dielectric solvent other than a lipophilic species according to the
invention is ethanol, ethyl acetate, isopropyl alcohol, triacetin,
triethyl citrate, tributyl citrate, a polyethylene glycol,
propylene glycol, bisabolol, glycerin, mineral oil, ethyl oleate, a
fatty acid ester, squalane, an animal oil, a vegetable oil, a
hydrogenated vegetable oil, isopropyl myristate, isopropyl
palmitate, glycofurol, a terepene, an essential oil, an alcohol, a
polyol, or a silicone fluid.
Solid Carrier. In an embodiment, a formulation according to the
invention contains a solid carrier. A liquid LA or LA-solvate
according to the invention is adsorbed or absorbed onto a solid
carrier to improve processing. When an ingredient is a liquid it is
typically necessary to convert it into a solid before blending it
with other powders to prepare tablets, capsules or other solid
dosage forms. The liquid is typically of an oily nature and can be
adsorbed onto the surface of a solid. Adsorption, being a surface
phenomenon, is influenced by the available surface area on the
solid. Thus, the most efficient adsorbents are usually very small
particles. In an embodiment, an adsorbent according the invention
may be microcrystalline celluloses, cellulose powder, silicified
microcrystalline celluloses (PROSOLV 50, PROSOLV 90HD), silicas
(ZEOPHARM 5170, AEROPERL 300, SYLOID 244FP, SYLOID 63FP, SYLOID 72
FP), clays, talc, starches, pregelatinized starches, calcium
carbonate, and magnesium carbonate. In one embodiment, a solid
carrier for a liquid LA according to the invention is a
cyclodextrin or a substituted cyclodextrin. These materials form
inclusion complexes with lipophilic molecules on a 1:1 molar ratio.
Cyclodextrins are "bucket like" molecules, with a ridged structure
and a central cavity. The internal surface of the central cavity is
lipophilic, while the outside surface is hydrophilic. This
arrangement allows the cyclodextrin to harbor a guest molecule
within the cavity, forming an inclusion complex that is
water-soluble. Thus, this mechanism of solidification is by
absorption.
Water-Soluble Excipient. In an embodiment, a formulation according
to the invention contains a water-soluble excipient. A variety of
excipients are useful as the water-soluble component of the
invention, the selection being based on the delivery system. In an
embodiment, the water-soluble excipient can be a water-soluble LA
solvent, e.g., propylene glycol for use in a liquid dosage form. In
an embodiment, the water-soluble excipient can be a tablet diluent,
e.g., mannitol for a solid dosage form. The development of a
gradually increasing hydration and dielectric gradient in the
dosage form is most favorable for transmucosal delivery of an
ionizable pharmaceutical agent according to the invention. Hence,
in an embodiment, a water-soluble excipient according to the
invention is one or more of the following: a sugar, a polyol, a
alcohol, a saccharide, a polysaccharide, glycerin, propylene
glycol, ethanol, isopropyl alcohol, ethyl acetate, triacetin,
triethyl citrate, tributyl citrate, a dextrate, a dextrin,
dextrose, fructose (ADVANTOSE FS 95), lactitol (FINLAC DC),
lactose, erythritol, maltose, maltitol, a maltodextrin, a
polydextrose, trehalose, mannitol (PEARLITOL 300 DC, PEARLITOL 400
DC, PEARLITOL 500 DC, MANNOGEM 2080, MANNOGEM EZ, PARTEK M200,
PARTEK M300), a polyethylene glycol, sorbitol, sucrose and xylitol
(XYLITOL 200, XYLITOL 300).
Other Excipients. In an embodiment, another excipient, chosen to
enhance processability, form, function or appeal of the formulation
is included in a formulation according to the invention. In such an
embodiment, another excipient according to the invention is a
buffering agent (such as phosphate, carbonate, tartrate, borate,
citrate, acetate, and maleate buffers), colorant, flavoring,
solvent and co-solvent, coating agent, binder, diluent, carrier,
disintegrant, glident, lubricant, opacifying agent, humectant,
granulating agent, gelling agent, polishing agent, suspending
agent, sweetening agent, anti-adherent, preservative, emulsifying
agent, antioxidant, levigating agent, plasticizer, surfactant,
tonicity agent, viscosity agent, enteric agent and coating,
controlled-release agent and coating, wax, wetting agent,
thickening agent, suppository base, stiffing agent, stabilizing
agent, solubilizing agent, sequestering agent, ointment base,
oleaginous vehicle, film-forming agent, essential oil, emollient,
dissolution enhancer, dispersing agent, and/or cryoprotectant or
combinations thereof.
EXEMPLARY EMBODIMENTS
Sublingual/Buccal Tablets
It will be readily understood that the components, formulations,
processes, and methods of use of the present invention, as
generally described herein, are arranged and designed in a wide
variety of different dosage forms and formulations. Thus, the
following more detailed description of the embodiments of the
formulation and methods of use of the present invention is not
intended to limit the scope of the present invention, as claimed,
but merely represents one of the dosage form embodiments of the
invention, e.g. a sublingual/buccal tablet.
Example I
Nicotine
In an embodiment, a buccal/sublingual tablet formulation according
to the invention is useful in nicotine replacement therapy (NRT).
Certain commercially available products for NRT in smoking
cessation, such as patches, gum, and lozenges, do not provide for
the rapid rise or peak nicotine plasma levels obtained by smoking.
Certain other products, such as nasal sprays, inhalers, and certain
sublingual tablets, that attempt to provide nicotine plasma levels
similar to smoking a cigarette, result in local irritation.
Pomerleau (Ann. Behav. Med. 1998, Vol. 36, 158-163) listed criteria
for a successful NRT: 1) the method should be safe and easy to use;
2) specific doses should be accurately and reproducibly delivered;
3) the pharmacokinetics should resemble those of cigarette smoking.
Judging from the very limited efficacy of the current commercial
NRTs (typically less than 20%), current commercial NRTs are not
meeting the Pomerleau criteria.
However, an embodiment of the present invention did meet the
Pomerleau criteria. One embodiment of the present invention
provides a convenient, small, round sublingual/buccal tablet useful
for NRT. Such a tablet rapidly dissolved under the tongue or
dissolved more slowly in the buccal cavity between the gums and
cheek. Further, it did not produce ulcers in the mouth, which is
one of the undesired side effects of other formulations that use
nicotine in its free base form. It was also convenient and easy to
use and is a socially acceptable delivery system. It is much more
like taking a breath mint, unlike nasal sprays or inhalers.
Further, such a tablet reproducibly provided a rapid bolus of
nicotine after sublingual administration. Hence a sublingual/buccal
tablet according to the invention meets the Pomerleau criteria and
is more successful at helping smokers quit cigarettes than the
currently marketed products.
In one embodiment, the invention provided a 2 mg strength nicotine
sublingual/buccal tablet having a total tablet weight around 50 mg
and nominal dimensions of about 0.55 cm in diameter and a thickness
of about 0.15 cm. In such an embodiment, the ionic pharmaceutical
agent according to the invention contained nicotine and a
lipophilic species. The lipophilic species was oleic acid. The
molar ratio of lipophilic species to ionic pharmaceutical agent was
not less than about 1:1. However, a molar excess of the lipophilic
species, in this example oleic acid, may be used, e.g., 1.2:1, but
is not limited to this ratio. This LA is a liquid at room
temperature. In order to convert the LA into a flowable powder
suitable for use in direct compression tableting required the use
of an adsorbent/absorbent, such as silica. In order to manufacture
a rapidly disintegrating, directly compressible tablet other
excipients were needed. For example, the diluent may be the
water-soluble, direct compression tableting excipient mannitol. A
disintegrant is included to rapidly break the tablet apart upon
administration. An exemplary disintegrant is sodium starch
glycolate. An exemplary tablet lubricant is sodium stearyl
fumarate. A quantitative formulation is given in Table I.
TABLE-US-00001 TABLE I 2 mg Nicotine Sublingual/Buccal Tablet
Formulation INGREDIENT AMOUNT (mg/tablet) Nicotine 2.0 Oleic Acid
3.5 Silica 4.0 Mannitol 38.5 Sodium Starch Glycolate 1.5 Sodium
Stearyl Fumarate 0.5 Total Tablet Weight 50.0
A method of manufacture for a sublingual/buccal tablet according to
the invention is a suitable method known in the art, such as the
addition of the nicotine LA or LA-solvate to premanufactured
tablets, cold compressions with inert fillers and binders, direct
tablet compression blends, direct powder blends, wet or dry
granulations, molding, lyophilization, microencapsulation, co-melt,
freeze drying, spray-congealing, spray-drying, spheronization,
triturates, troching, powder layering, pelleting, encapsulation. An
exemplary method of manufacture is outlined below and schematically
in FIG. 1.
STEP 1: Mix nicotine and oleic acid together until homogeneous, to
form a nicotine LA.
STEP 2: Blend the nicotine LA with silica until homogeneous to form
a nicotine LA silica carrier blend.
STEP 3: Add the nicotine LA silica carrier blend to mannitol and
sodium starch glycolate and blend until homogeneous to form a
further blend.
STEP 4: Add sodium stearyl fumarate to the further blend and blend
until well lubricated to form a lubricated blend.
STEP 5: Compressing the lubricated blend into tablets using 7/32''
round tooling.
Method of packaging. The sublingual/buccal tablets may be packaged
in such a manner as to aid in maintaining nicotine stability.
Exemplary packaging methods and materials include, but are not
limited to, blister packaging in a foil/foil, foil/Acrylonitrile,
foil/Polychlorotrifluoroethylene laminates.
Comparative dissolution. Drug dissolution is a prerequisite to drug
absorption and clinical response for almost all drugs given orally.
(G. L. Amidon, H. Lennemas, V. P. Shah, J. R. Crison, "A
Theoretical Basis for a Biopharmaceutical Drug Classification: The
Correlation of in Vitro Drug Product Dissolution and in Vivo
Bioavailability," Pharm. Res. 1995, Vol. 12, No. 3, pp 413-420.)
Dissolution is considered an in vitro technique that gives good
correlation to a product's in vivo performance. A drug must first
be released from the delivery system in order to be available for
absorption. Therefore, tablets having a faster dissolution would be
expected to have faster absorption in vivo. FIG. 2 presents the
dissolution results of the nicotine sublingual/buccal tablet, the
embodiment of the invention as presented herein, and two nicotine
commercial products, i.e., a lozenge (COMMIT.TM. and a sublingual
tablet MICROTAB.TM.). Dissolution was conducted in 900 ml of D.I.
water at 50 RPM using USP Apparatus 2. Samples were pulled at 2, 5,
10, 20, 30, 40 and 60 minutes, and analysis was by HPLC.
As can be seen from the dissolution profiles, the sublingual/buccal
tablet released over 90% of the nicotine in the tablet within 10
minutes. This rapid release of nicotine corresponded to typical
plasma nicotine levels obtained from smoking a cigarette, which
peak in about 10 minutes (WO 03/055486 A1). The lozenge COMMIT.TM.
shows a very slow profile releasing only 35% of the dosage at the
end of 60 minutes. The other sublingual tablet, MICROTAB.TM., takes
about 30 minutes to reach the same level that the embodied
invention given herein reached within 10 minutes, i.e., 90% of the
dosage dissolved.
The other products fail to provide rapid nicotine release, and
therefore cannot provide a nicotine plasma level comparable to what
a person obtains from smoking a cigarette. The present invention as
embodied herein did provide rapid nicotine release. Indeed, more
than 90% of the nicotine in the tablet was dissolved and available
for transmucosal absorption within 10 minutes. It should be noted
that the pH of the dissolution media obtained after dissolution of
the sublingual/buccal tablets as embodied in this invention was
6.2. This is very similar to the pH of saliva, which is general
recognized as being around 6.8. At a pH of 6.8 only about 10% of
the nicotine is in the free base form. Others have indicated that
in order to promote absorption of nicotine through the oral mucosa,
the pH of the saliva must be increased so that nicotine will be
predominately in the free base form (WO 03/055486 A1). The present
invention provides for nicotine transmucosal absorption in acidic
conditions similar to the physiological pH of the saliva. Others
indicated that such a low pH nicotine transmucosal delivery would
not be efficacious.
In Vivo Data: Two male volunteers and one female volunteer, all
former smokers, placed the nicotine sublingual tablet, as embodied
herein, under the tongue and left it undisturbed. Immediately upon
administration a tingling sensation was very apparent in the area
where the sublingual tablet was placed. Shortly thereafter, i.e.,
within a few minutes, the physiological effects of nicotine were
very apparent to all three volunteers. This included being
light-headed, dizzy, a warning sensation and an increase in heart
rate. In all three volunteers, the symptoms peaked within 10
minutes and the tablets were totally dissolved in less than 5
minutes. Interestingly, the usually overwhelming acrid taste of
nicotine was not apparent. Instead there was a slightly bitter
taste that was complimented by the sweet taste of mannitol. Within
30 minutes all volunteers felt normal. All three volunteers stated
that the nicotine sublingual tablet, as embodied herein, provided a
bolus of nicotine that was similar to that obtained from smoking a
cigarette.
Method of Use: In an exemplary embodiment, a buccal/sublingual
tablet formulation according to the invention is useful in nicotine
replacement therapy (NRT). This therapy is designed to allow
smokers to quit smoking by providing nicotine in a non-carcinogenic
delivery system, i.e., without tars. In a typical treatment
regiment, the smoker starts by placing a 2 or 4 mg nicotine
sublingual tablet under the tongue and leaving it undistributed
until dissolved, typically within 5 minutes, whenever there is an
urge to smoke. In one embodiment, about 10 to 30 sublingual tablets
are used per day. After a period of several weeks, the dosage is
lowered to 2 mg or 1 mg (depending on the starting strength) then
to 0.5 mg. Eventually, a placebo is used, if required. This gradual
reduction in nicotine content helps wean the smoker off the desire
for nicotine. This is usually supplemented with counseling. The
tablets of the present invention can also be used by smokers when
it is not acceptable for them to smoke, e.g., when they are in an
airplane. The dosage range for this embodiment may be from 0.5 mg
to 5 mg of nicotine.
Example II
Epinephrine
Epinephrine (adrenaline) is commonly given by subcutaneous or
intramuscular injection for anaphylactic shock, allergic reactions
and acute asthmatic attacks. The usual dosage is 300 .mu.g, given
intramuscularly by use of an auto-injector. Patients with a history
of severe allergic reactions to insect bites or stings, foods,
drugs, and other allergens, as well as idiopathic and exercise
induced anaphylaxis, are supplied with auto-injectors for
intramuscular self-administration. This is the preferred treatment
for serious allergic reactions. An embodiment according to the
invention, an epinephrine sublingual/buccal tablet as described
below, has several advantages over the current therapy. First, the
invention as embodied herein is convenient, non-invasive and
painless to administer. Further, epinephrine is also unstable in
light and is readily oxidized; an embodiment according to the
invention, as described below, being a solid-state product rather
than liquid preparation, provides better stability.
In such an embodiment, the invention provides a 300 .mu.g strength
epinephrine sublingual/buccal tablet having a total tablet weight
around 50 mg and nominal dimensions of about 0.55 cm in diameter
and a thickness of about 0.15 cm. In such an embodiment, the ionic
pharmaceutical agent according to the invention contains
epinephrine and the lipophilic species with which it is combined
(such as oleic acid), the molar ratio of the lipophilic species to
ionic pharmaceutical agent being not less than about 1:1. However,
a molar excess of the lipophilic species, in this example oleic
acid, may be used, e.g., 1.2:1. Embodiments are described herein.
In certain embodiments, the LA may require the use of a solvent to
stabilize or solubilize the LA, e.g., ethyl oleate and polyethylene
glycol 400. Embodiments are described herein. In certain
embodiments, the liquid LA or LA-solvate requires the use of an
adsorbent/absorbent in order to convert it into a flowable powder
suitable for use in direct compression tableting (such as silica).
Other excipients are in some circumstances useful in order to
manufacture a rapidly disintegrating, directly compressible tablet
(such as the water-soluble, direct compression tableting excipient
mannitol). In order to rapidly break the tablet apart upon
administration, a disintegrant is used. In one embodiment the
disintegrant is sodium starch glycolate. An exemplary tablet
lubricant is sodium stearyl fumarate. Exemplary embodiments are
provided in Table II.
TABLE-US-00002 TABLE II 300 .mu.g Epinephrine Sublingual/Buccal
Tablet Formulations AMOUNT AMOUNT AMOUNT (mg/tablet) (mg/tablet)
(mg/tablet) Embodiment Embodiment Embodiment INGREDIENT 1 2 3
Epinephrine 0.30 0.30 0.30 Oleic Acid 0.46 0.46 0.46 Ethyl oleate
-- 4.74 -- Polyethylene glycol 400 -- -- 4.74 Silica 0.55 4.00 4.00
Mannitol 46.69 38.50 38.50 Sodium Starch Glycolate 1.50 1.50 1.50
Sodium Stearyl Fumarate 0.50 0.50 0.50 Total Tablet Weight 50.00
50.00 50.00
Method of manufacture. A method of manufacture for such
sublingual/buccal tablet embodiments may be any suitable method
known in the art including, but not limited to, the addition of the
epinephrine LA or LA-solvate to premanufactured tablets, cold
compressions with inert fillers and binders, direct tablet
compression blends, direct powder blends, wet or dry granulations,
molding, lyophilization, microencapsulation, freeze drying,
spray-congealing, spray-drying, co-melt, spheronization,
triturates, troching, powder layering, pelleting, encapsulation. An
exemplary method of manufacture is outlined below and is
schematically diagramed in FIG. 3.
STEP 1: Mix epinephrine, oleic acid and any other solvents together
to form a solution. STEP 2: Blend the epinephrine LA or LA-solvate
with silica until homogeneous to form a silica carrier blend. STEP
3: Add the silica carrier blend to mannitol and sodium starch
glycolate and mix until homogeneous to form a further blend. STEP
4: Add sodium stearyl fumarate to the further blend and blend until
well lubricated to form a lubricated blend. STEP 5: Compressing the
lubricated blend into tablets using 7/32'' round tooling.
Method of packaging. The sublingual/buccal tablets may be packaged
in such a manner as to aid in maintaining epinephrine stability.
Packaging methods and materials may include, but are not limited
to, blister packaging in a foil/foil, foil/Acrylonitrile,
foil/Polychlorotrifluoroethylene laminates.
Method of Use: In an embodiment, a buccal/sublingual tablet
formulation according to the invention is useful in the treatment
of severe allergic reactions to insect bites or stings, foods,
drugs, and other allergens, as well as idiopathic and exercise
induced anaphylaxis. This therapy is designed to allow allergic
patient to abort a hyper immune response such as anaphylaxis. The
typical treatment regiment starts by placing a 300 .mu.g
epinephrine sublingual tablet under the tongue and leaving it
undistributed until dissolved, typically within 5 minutes, whenever
there is an allergic reaction. This can be supplemented with
additional sublingual tablets until the allergic response is
ameliorated. The dosage range for this embodiment may vary from 200
ug to 1000 ug.
Example III
Fentanyl
Fentanyl transmucosal delivery is first line therapy for management
of breakthrough cancer pain in patients with malignancies who are
already tolerant to opioid therapy for their underlying persistent
cancer pain. The embodiments as given herein have several
advantages over the current therapy. First, the current
transmucosal therapy uses a lollipop as the delivery system. The
inherent implication and dangers of placing a potent opiate in the
form of a candy attractive to children cannot be trivialized.
Further, the current therapy takes over 20 minutes to reach maximum
plasma concentrations. Thus pain relief is delayed far longer than
would be desired. Hence the invention provides, in an embodiment, a
fentanyl sublingual/buccal tablet to rapidly dissolve under the
tongue, providing fast onset of action and pain relief for a cancer
patient. Further, it is much safer for the family environment than
a lollipop, which requires the disposal of potent, opioid-laden
delivery systems.
In one embodiment, the invention provides a 200 ug strength
fentanyl sublingual/buccal tablet having a total weight around 50
mg and nominal dimensions of about 0.55 cm in diameter and a
thickness of about 0.15 cm. In one embodiment, the ionic
pharmaceutical agent is fentanyl and the lipophilic species with
which it is combined is oleic acid. The molar ratio of the
lipophilic species to ionic pharmaceutical agent in this embodiment
is not less than about 1:1. However, a molar excess of the
lipophilic species, in this example oleic acid, may be used, e.g.
1.2:1. Embodiments are described herein. In certain embodiments,
the LA may require the use of a solvent to stabilize or solubilize
the LA, e.g. ethyl oleate and polyethylene glycol 400. In certain
embodiments, the liquid LA or LA-solvate requires the use of an
adsorbent/absorbent in order to convert it into a flowable powder
suitable for use in direct compression tableting. An exemplary
adsorbent is a silica Other excipients may be used in order to
manufacture a rapidly disintegrating, directly compressible tablet.
An exemplary diluent is the water-soluble, direct compression
tableting excipient mannitol. In order to rapidly break the tablet
apart upon administration, a disintegrant is used. An exemplary
disintegrant is sodium starch glycolate. An exemplary tablet
lubricant is sodium stearyl fumarate. Exemplary embodiments are
provided in Table III.
TABLE-US-00003 TABLE III 200 .mu.g Fentanyl Sublingual/Buccal
Tablet Formulations AMOUNT AMOUNT AMOUNT (mg/tablet) (mg/tablet)
(mg/tablet) Embodiment Embodiment Embodiment 1 2 3 Fentanyl 0.20
0.20 0.20 Oleic Acid 0.17 0.17 0.17 Ethyl oleate -- 5.13 --
Polyethylene glycol 400 -- -- 5.13 Silica 0.27 4.00 4.00 Mannitol
47.36 38.50 38.50 Sodium Starch Glycolate 1.50 1.50 1.50 Sodium
Stearyl Fumarate 0.50 0.50 0.50 Total Tablet Weight 50.00 50.00
50.00
Method of manufacture. A method of manufacture for such
sublingual/buccal tablet embodiments may be any suitable method
known in the art including, but not limited to, the addition of the
fentanyl LA or LA-solvate to premanufactured tablets, cold
compressions with inert fillers and binders, direct tablet
compression blends, direct powder blends, wet or dry granulations,
molding, lyophilization, microencapsulation, freeze drying,
spray-congealing, spray-drying, co-melt, spheronization,
triturates, troching, powder layering, pelleting, encapsulation. An
exemplary method of manufacture is outlined below and is
schematically represented in FIG. 4.
STEP 1: Mix fentanyl, oleic acid and any other solvents together to
form a solution. STEP 2: Blend the fentanyl LA or LA-solvate with
silica until homogeneous to form a silica carrier blend. STEP 3:
Add the silica carrier blend to mannitol and sodium starch
glycolate and mix until homogeneous to form a further blend. STEP
4: Add sodium stearyl fumarate to the further blend and blend until
well lubricated to form a lubricated blend. STEP 5: Compressing the
lubricated blend into tablets using 7/32'' round tooling.
Method of packaging. The sublingual/buccal tablets may be packaged
in such a manner as to aid in maintaining fentanyl stability.
Exemplary packaging methods and materials include, but not limited
to, blister packaging in a foil/foil, foil/Acrylonitrile,
foil/Polychlorotrifluoroethylene laminates.
Method of Use: In an embodiment, a buccal/sublingual tablet
formulation according to the invention is useful in the treatment
of severe breakthrough cancer pain in patients with malignancies
who are already tolerant to opioid therapy for their underlying
persistent cancer pain. This therapy is designed to allow the
cancer patient to self-administer the treatment. The treatment
regiment starts by placing a 200 ug fentanyl sublingual tablet
under the tongue and leaving it undistributed until dissolved,
typically within 5 minutes, whenever there is an occurrence of
breakthrough pain. Depending on the level of opiate tolerance in
each patient, other dosage strengths may be used in treatment of
each individual patient. The range of dosage strength can be from
50 ug to 5000 ug.
Example IV
Alendronic Acid
Bisphosphonates are potent inhibitors of bone resorption and are
used in osteoporosis and Paget's disease of the bone. These are
also used in the treatment of bone metastases and hypercalcaemia of
malignancies. The most commonly used bisphosphonates are alendronic
acid, clodronic acid and etidronic acid. The embodiments as given
herein have several advantages over the current bisphosphonate
therapies. First, the current therapy is a tablet given by mouth or
by IV injection. Oral administration is associated with a number of
severe side effects including oesophagitis, esophageal erosions and
ulcerations, dyspepsia, diarrhea, abdominal pain, and peptic
ulcers. Further, oral bioavailability is very poor, in the range of
0.4 to 0.7% for alendronic acid and from to 1 to 6% for clodronic
and etidronic acids. When administrated with food, bioavailability
can be significantly reduced even to the level of being negligible.
For alendronic acid, the usual daily dosage is 5 to 10 mg for
osteoporosis and the dosage for Paget's disease is about 40 mg per
day. The present invention provides, in one embodiment, a
sublingual/buccal tablet that is designed to rapidly dissolve under
the tongue. This avoids the potentially serious side effects and
the poor and erratic bioavailability observed from oral
delivery.
In one embodiment, a 100 .mu.g strength alendronic
sublingual/buccal tablet has a total weight of about 50 mg, and
nominal dimensions of about 0.55 cm in diameter and a thickness of
about 0.15 cm. The ionic pharmaceutical agent in this example is
alendronic acid combined with the lipophilic species oleic acid.
Alendronic acid has an amine functional group in additional to acid
functional groups in addition to acid functional groups. The molar
ratio between these two species in this example is at least about
1:1. However, since alendronic acid contains two phosphoric acid
groups, a lipophilic amine or amide, in this example hexetidine,
may need. The molar ratio is at least about 1:1 but may be
increased to about 2:1. In certain embodiments, the LA may require
the use of a solvent to stabilize or solubilize the LA, e.g., ethyl
oleate and polyethylene glycol 400. Embodiments are described
herein. The LA or LA-solvate may require the use of an
adsorbent/absorbent in order to convert it into a flowable powder
suitable for use in direct compression tableting. In one
embodiment, the adsorbent is a silica. In order to manufacture a
rapidly disintegrating, directly compressible tablet other
excipients may be needed. In one embodiment, the diluent is the
water-soluble, direct compression tableting excipient mannitol. In
order to rapidly break the tablet apart upon administration, a
disintegrant is used. In one embodiment, the disintegrant is sodium
starch glycolate. In one embodiment, the tablet lubricant is sodium
stearyl fumarate. Several embodiments are given in Table IV.
TABLE-US-00004 TABLE IV 100 .mu.g Alendronic Acid Sublingual/Buccal
Tablet Formulations AMOUNT AMOUNT AMOUNT AMOUNT (mg/tablet)
(mg/tablet) (mg/tablet) (mg/tablet) Embodiment Embodiment
Embodiment Embodiment INGREDIENT 1 2 3 4 Alendronic 0.10 0.10 0.10
0.10 acid Oleic acid 0.12 0.13 0.13 0.13 Hexetidine -- 0.27 0.27
0.27 Ethyl oleate -- -- 5.00 -- Polyethylene -- -- -- 5.00 glycol
400 Silica 0.13 0.35 4.00 4.00 Mannitol 47.65 47.16 38.51 38.51
Sodium Starch 1.50 1.50 1.50 1.50 Glycolate Sodium Stearyl 0.50
0.50 0.50 0.50 Fumarate Total Tablet 50.00 50.00 50.00 50.00
Weight
Method of Manufacture
The method of manufacture for this sublingual/buccal tablet
embodiment may be any suitable method know in the art including,
but not limited to, the addition of the alendronic acid LA or
LA-solvate to premanufactured tablets, cold compressions with inert
fillers and binders, direct tablet compression blends, direct
powder blends, wet or dry granulations, molding, co-melt,
lyophilization, microencapsulation, freeze drying,
spray-congealing, spray-drying, spheronization, triturates,
troching, powder layering, pelleting, encapsulation. One exemplary
method of manufacture is outlined below and is schematically in
FIG. 5.
STEP 1: Mix alendronic acid, oleic acid, and any other the
lipophilic species or solvents together to form a solution. STEP 2:
Blend the alendronic acid LA or LA-solvate with silica until
homogeneous to form a silica carrier blend. STEP 3: Add the silica
carrier blend to mannitol and sodium starch glycolate and mix until
homogeneous to form a further blend. STEP 4: Add sodium stearyl
fumarate to the further blend and blend until well lubricated to
form a lubricated blend. STEP 5: Compressing the lubricated blend
into tablets using 7/32'' round tooling.
Method of Packaging: The sublingual/buccal tablets may be packaged
in such a manner as to aid in maintaining stability. Exemplary
packaging methods and materials include blister packaging in a
foil/foil, foil/Acrylonitrile, foil/Polychlorotrifluoroethylene
laminates.
Method of Use: In an embodiment, a buccal/sublingual tablet
formulation according to the invention is useful in the treatment
of osteoporosis and Paget's disease of the bone. It can also be
used in the treatment of bone metastases and hypercalcaemia of
malignancies. In one embodiment the treatment regiment starts by
placing a 100 .mu.g alendronic acid sublingual tablet under the
tongue and leaving it undistributed until dissolved, typically
within 5 minutes. The treatment is given once a day. The dosage
range for this embodiment may be from 50 .mu.g to 1000 .mu.g.
Example V
Clorazepic Acid
Clorazepic acid is a benzodiazepine used mainly for the treatment
of anxiety, adjunct therapy for epilepsy and alcohol withdrawal
syndrome. It is administered orally, intravenously and
intramuscularly. Orally it is typically given in divided doses. The
embodiments as given herein have several advantages over the
current therapies. A patient undergoing alcohol withdrawal will
typically exhibit signs of nausea and vomiting. Any orally
administrated therapy during times of alcohol withdrawal runs the
risk of being not efficacious as vomiting can eliminate the dosage.
Further, for children, geriatric and depilated patients, swallowing
a tablet can be difficult. Since clorazepic acid is used in the
relief of anxiety for elderly and debilitated patients and also as
an adjunct therapy for epilepsy in children, having a convenient
dosage form that does not require swallowing a tablet for
administration provides a better therapy. Another therapy for which
benzodiazepines have been used is for panic attacks. Sublingual
clorazepic may be useful in the treatment of panic attacks,
particularly due to its rapid onset of action. Panic attacks and
agoraphobia could be avoided by administered the sublingual tablet
just prior to the patient encountering a situation known to induce
such attacks. Further, it could be used at the first signs of an
attack, due to its rapid absorption, and thereby abort the
attack.
In one embodiment, a 5.75 mg strength clorazepic acid
sublingual/buccal tablet has a total weight around 100 mg, and
nominal dimensions of about 0.64 cm in diameter and a thickness of
about 0.20 cm. The ionic pharmaceutical agent is clorazepic acid
combined with the lipophilic species hexetidine. The molar ratio
between these two species being not less than about 1:1. This LA
may also require the use of a solvent. The LA or LA-solvate may
require the use of an adsorbent/absorbent in order to convert it
into a flowable powder suitable for use in direct compression
tableting. One exemplary adsorbent for this embodiment is a silica.
In order to manufacture a rapidly disintegrating, directly
compressible tablet, other excipients may be needed. In one
embodiment the diluent is the water-soluble, direct compression
tableting excipient mannitol. In order to rapidly break the tablet
apart upon administration a disintegrant is used. In one
embodiment, the disintegrant is sodium starch glycolate. In one
embodiment, the tablet lubricant is sodium stearyl fumarate.
Several embodiments, are given in Table V below.
TABLE-US-00005 TABLE V 5.75 mg Clorazepic Acid Sublingual/Buccal
Tablet Formulations AMOUNT AMOUNT AMOUNT (mg/tablet) (mg/tablet)
(mg/tablet) Embodiment Embodiment Embodiment INGREDIENT 1 2 3
Clorazepic acid 5.75 5.75 5.75 Hexetidine 6.25 6.25 6.25 Ethyl
oleate -- 2.00 -- Polyethylene glycol 400 -- -- 2.00 Silica 8.00
9.00 9.00 Mannitol 76.00 73.00 73.00 Sodium Starch Glycolate 3.00
3.00 3.00 Sodium Stearyl Fumarate 1.00 1.00 1.00 Total Tablet
Weight 100.00 100.00 100.00
Method of Manufacture: The method of manufacture for this
sublingual/buccal tablet embodiment may be any suitable method know
in the art including, but not limited to, the addition of the
clorazepic acid LA or LA-solvate premanufactured tablets, cold
compressions with inert fillers and binders, direct tablet
compression blends, direct powder blends, wet or dry granulations,
molding, spray-congealing, lyophilization, freeze-drying,
microencapsulation, co-melt, spray-drying, spheronization,
triturates, troching, powder layering, pelleting, encapsulation.
One method of manufacture is outlined below and is schematically
represented in FIG. 6.
STEP 1: Mix clorazepic acid, hexetidine and any other solvents
together until a solution is prepared. STEP 2: Blend the clorazepic
acid LA or LA-solvate with silica until homogeneous. STEP 3: Add
the clorazepic LA or LA-solvate silica carrier blend to mannitol
and sodium starch glycolate and mix until homogeneous. STEP 4: Add
sodium stearyl fumarate to the blend from Step 3 and blend until
well lubricated. STEP 5: The lubricated blend from Step 4 is
compressed into tablets using 1/4'' round tooling.
Method of Packaging: The sublingual/buccal tablets may be packaged
in such a manner as to aid in maintaining stability. Exemplary
packaging methods and materials include, but are not limited to,
blister packaging in a foil/foil, foil/Acrylonitrile,
foil/Polychlorotrifluoroethylene laminates.
Method of Use: In an embodiment, a sublingual/buccal tablet
formulation according to the invention is useful in the treatment
of alcohol withdrawal, anxiety or epilepsy. This therapy is
designed to allow the patient to administer the therapy without
having to swallow the dosage form. The typical treatment regiment
starts by placing a 5.75 mg clorazepic acid sublingual tablet under
the tongue and leaving it undistributed until dissolved, typically
within 5 minutes. This can be supplemented with additional
sublingual tablets during the day, typically three times per day;
however, under certain treatment regiments one tablet at night may
be given. For panic attacks and agoraphobia, the patient can
administer the sublingual tablet just prior to encountering a
panic-inducing situation or at the onset of an attack. The dosage
range for this embodiment can be from 2 mg to 12 mg of clorazepic
acid.
In one embodiment, the pharmaceutical composition of the subject
invention is provided as an oral solid dosage form for buccal or
sublingual administration, e.g. films, lozenges, pills and tablets.
In the following illustrative embodiments, the oral dosage form is
provided as a tablet. In the following illustrative embodiments,
the treatment is directed to subjects with tobacco dependence or
other indications for which nicotine can be used as a therapeutic
and wherein increasing the oral absorption and bioavailability,
while shortening the onset of nicotine action is provided.
It is understood by the skilled artisan, that use of the term
"about" includes the range as stated, are within what is normally
acceptable in the pharmaceutical industry. The US Pharmacopeia
allows a plus and minus range of 10% in the assay for the active
ingredient in most solid dosage forms. The Food and Drug
Administration (FDA) has a published Guidances for changes in
levels of common excipient classes that are considered unlikely to
have any detectable impact on formulation quality and performance
(Guidance for Industry: Immediate Release Solid Oral Dosage Forms
Scale-Up and Post approval Changes: Chemistry, Manufacturing, and
Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence
Documentation). Under this Guidance the water-soluble solid
excipient has an allowable change is .+-.5%, for a disintegrant it
is .+-.1%, for a lubricant it is .+-.1%. Although the Guidance is
not specific for the complimentary lipophilic species, co-solvent
or adsorbent and considering the range for the active is .+-.10%,
the value for these excipients should be no different than the
active as their use in the formulation is directly dependent on the
active's level.
As illustrated, tablets are used for the treatment and such tablets
contain from about 0.1 mg to about 5 mg of nicotine, from about
0.15 mg to about 10 mg of a complimentary lipophilic species,
illustrated by, albeit not limited to, oleic acid, from about 0.1
mg about 50 mg of a solid adsorbent, when included in a particular
formulation, illustrated by, albeit not limited to silica, and from
about 25 mg to about 500 mg of a water-soluble solid excipient,
illustrated by, albeit not limited to, spray dried mannitol. In
some instances the water-soluble solid excipient, illustrated by,
albeit not limited to, spray dried mannitol, may function as the
only solid adsorbent and as the water-soluble solid excipient in
the particular formulation. In the case of certain formulations, an
effective amount of a co-solvent may be necessary in order to
enhance the transport of the active ingredient through the mucosal
membrane. In such instances up to 5 mg per tablet is considered an
effective amount to facilitate such transport, illustrated by,
albeit not limited to ethanol.
In the illustrated embodiments, the tablet further contains at
least one disintegrant and one lubricant. Although the disintegrant
has been exemplified in the formulations in Table 6, 7 and 8 as
sodium starch glycolate, it is nevertheless within the purview of
this invention to substitute any functionally equivalent
disintegrant, illustrated by, but not limited to, crospovidone,
croscarmellose sodium, low-substituted hydroxypropyl cellulose,
starch, microcrystalline cellulose and mixtures thereof. The
content of the disintegrant is from about 0.5 mg to about 50
mg.
In the illustrated embodiments, the tablet further contains at
least one lubricant. Although the lubricant has been exemplified in
the formulations in Table 6, 7 and 8 as sodium stearyl fumarate, it
is nevertheless within the purview of this invention to substitute
any functionally equivalent lubricant, illustrated by, but not
limited to, magnesium stearate, stearic acid, sodium lauryl
sulfate, talc, polyethylene glycol, calcium stearate and mixtures
thereof. The content of the lubricant is from about 0.1 mg to about
15 mg.
Example VI
In one embodiment, the invention provides a 2 mg strength nicotine
sublingual tablet having a total tablet weight of about 50 mg,
wherein the tablet comprises nicotine, a solid adsorbent, such as
silica; a water-soluble solid excipient, such as mannitol; a
disintegrant, such as sodium starch glycolate; and a lubricant,
such as sodium stearyl fumarate. In such an embodiment, nicotine is
mixed with oleic acid. An exemplary formulation in accordance with
the described formulation of this embodiment is provided in Table
VI, below.
TABLE-US-00006 TABLE VI 2 mg Nicotine Sublingual Tablet Formulation
INGREDIENT AMOUNT (mg/tablet) Nicotine 2.0 Oleic acid 3.5 Silica
4.0 Mannitol 38.5 Sodium Starch Glycolate 1.5 Sodium Stearyl
Fumarate 0.5 Total Tablet Weight 50.0
Example VII
In one embodiment, the invention provides a 1 mg strength nicotine
sublingual tablet having a total tablet weight of about 74 mg. In
this exemplary embodiment, nicotine is mixed with oleic acid and
the co-solvent ethanol. An exemplary formulation manufactured for
this embodiment in accordance with the subject invention is
provided in Table VII, below.
TABLE-US-00007 TABLE VII 1 mg Nicotine Sublingual Tablet
Formulation INGREDIENT AMOUNT (mg/tablet) Nicotine 1.0 Oleic Acid
1.7 Ethanol 0.5 Silica 2.3 Mannitol 65.0 Sodium Starch Glycolate
2.0 Sodium Stearyl Fumarate 1.5 Total Tablet Weight 74.0
Example VIII
In one embodiment, the invention provides a 0.5 mg strength
nicotine sublingual tablet having a total tablet weight of about
102 mg. In this exemplary embodiment, nicotine is mixed with oleic
acid and added to spray dried mannitol, which functions as the
water-soluble solid excipient and solid adsorbent. An exemplary
formulation manufactured for this embodiment in accordance with the
subject invention is provided in Table VIII, below.
TABLE-US-00008 TABLE VIII 0.5 mg Nicotine Sublingual Tablet
Formulation INGREDIENT AMOUNT (mg/tablet) Nicotine 0.5 Oleic Acid
1.0 Mannitol 95.5 Sodium Starch Glycolate 3.0 Sodium Stearyl
Fumarate 2.0 Total Tablet Weight 102.0
Example IX
The rate of drug release from a dosage form is a prerequisite for
systemic absorption. Dissolution study comparing a 2 mg sublingual
nicotine tablet prepared in accordance with Example VI of the
instant invention to the current art represented by 2 mg sublingual
nicotine tablet MicroTab.RTM. marketed by McNeil, a Johnson &
Johnson company. FIG. 7 shows the invention released nicotine much
faster than MicroTab.RTM., resulting in about 90% release in 10
minutes compared to taking about 30 minutes for MicroTab.RTM..
Although drug dissolution is a prerequisite to drug absorption it
is not very predictive of systemic absorption, pharmacokinetics or
bioavailability. However, in-vitro permeation studies are much more
predictive, wherein a drug's penetration through a relevant
biological membrane is measured. An oral mucosa permeation study
was conducted comparing 2 mg MicroTab.RTM. to a 2 mg nicotine
sublingual tablet according to Example VI. This study used oral
mucosal tissue mounted in a Franz cell and the drug concentration
was measured by high pressure liquid chromatograph (HLPC) in the
receiver solution over time. The tablets were wetted with 0.5 ml
water at the beginning of the test, and samples were taken from the
receiver side of the Franz cell over time. This data shows the
invention has much faster permeation through the mucosal tissue
compared to MicroTab.RTM., see FIG. 8. This shows that the
invention has faster absorption, higher bioavailability and a
faster onset of action compared to MicroTab.RTM..
Based on publically available information and actual human plasma
nicotine data from the administration of two 2 mg sublingual
tablets manufactured as per Example VI of the invention, a graph
has been prepared comparing the invention to representative
nicotine plasma concentrations obtained from two currently marketed
nicotine replacement therapies (NRTs), and cigarettes, see FIG. 9.
Note that the time to maximum plasma concentration (Tmax) occurs
between 5 and 15 minutes for cigarettes and the invention, compared
to about 60 minutes for Nicorette.RTM. gum and MicroTab.RTM.
sublingual tablet. This clearly demonstrates that the instant
invention increases oral absorption and bioavailability, while
shortening the onset of nicotine action. This graph also shows that
the invention mimics the nicotine plasma profile obtained from
smoking a cigarette and should therefore satisfy a smoker's
nicotine cravings.
FIG. 10 shows human plasma nicotine data and vital signs obtained
from the administration of two tablets prepared according to the
Example VI. This data shows that the time to maximum nicotine
plasma concentration (Tmax) occurred in about 7 minutes. The vital
sign data shows that the pulse and systolic/diastolic blood
pressure peak in less than 5 minutes after administration. Thus,
the physiological effects of nicotine are felt within a few
minutes, just like a cigarette.
The steps of dissolving the active ingredient, e.g. nicotine, to
form an active ingredient-containing solution followed by
contacting of the active ingredient-containing solution with the
solid absorbent/adsorbent carrier whereby said active
ingredient-containing solution is coated, absorbed or adsorbed onto
said carrier are unique to the instant invention, and the carrying
out of said steps are what allow for the formation of a unique
solid dosage form which enables increased oral absorption and
bioavailability while shortening onset of active ingredient action
upon administration of the novel solid dosage form via the buccal
or sublingual route.
Example X
A method of manufacture for a tablet according to an embodiment of
the subject invention for sublingual/buccal administration may
employ any suitable method known in the art including, but not
limited to, the addition of the nicotine and oleic acid mixture
with or without a co-solvent to pre-manufactured tablets, cold
compressions with inert fillers and binders, direct tablet
compression blends, direct powder blends, wet or dry granulations,
molding, lyophilization, microencapsulation, freeze drying,
spray-congealing, spray-drying, co-melt, spheronization,
triturates, troching, powder layering, pelleting,
encapsulation.
Outlined below and schematically diagramed in FIG. 1 is an
exemplary method for the manufacture of a direct compression tablet
of the formulation given in Example VI.
STEP 1: Mix nicotine and oleic acid together. STEP 2: Blend the
nicotine and oleic acid mixture from Step 1 with silica until
homogeneous to form a silica blend. STEP 3: Add to the silica blend
from Step 2, mannitol and sodium starch glycolate and mix until
homogeneous to form a further blend. STEP 4: Add sodium stearyl
fumarate to the further blend from Step 3 and blend until well
lubricated to form a lubricated blend. STEP 5: Compressing the
lubricated blend from Step 4 into 50 mg tablets using 7/16 inch
round tooling.
Method of packaging. The sublingual/buccal tablets may be packaged
in such a manner as to aid in maintaining stability. Packaging
methods and materials may include, but are not limited to, blister
packaging in a foil/foil, foil/Acrylonitrile,
foil/Polychlorotrifluoroethylene laminates for blister packaging or
glass and plastic bottles.
Method of Use: In an embodiment, nicotine sublingual tablet
formulation according to the invention is useful in the treatment
of tobacco dependence and other conditions and disease states for
which nicotine is an effective therapeutic. The typically treatment
regimen starts by placing the nicotine tablet under the tongue and
leaving it undisturbed for about 5 to 15 minutes.
All references cited herein are incorporated herein by reference.
Where the meaning of any term as used within the application itself
differs from the meaning of that same term in any of the
references, the meaning of the term as used within the application
itself controls.
It is to be understood that the embodiments described above are
intended to be illustrative and not restrictive. Many other
embodiments will be apparent to those of skill in the art once they
have read the above description. The foregoing description and
embodiments are therefore merely exemplary and are not intended to
limit the scope of the invention, which encompasses all equivalents
of what is described herein and set forth particularly by the
appended claims.
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